Human secreted proteins

ABSTRACT

The present invention relates to human secreted polypeptides, and isolated nucleic acid molecules encoding said polypeptides, useful for diagnosing and treating diseases, disorders, and/or conditions related to said human secreted proteins. Antibodies that bind these polypeptides are also encompassed by the present invention. Also encompassed by the invention are vectors, host cells, and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies. The invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

STATEMENT UNDER 37 C.F.R. §1.77(b)(4)

This application refers to a “Sequence Listing” listed below, which isprovided as an electronic document on two identical compact discs(CD-R), labeled “Copy 1” and “Copy 2.” These compact discs each containthe file “PS950D1_SeqList.txt” (7,281 bytes, created on Mar. 20, 2002),which is hereby incorporated in its entirety herein. The SequenceListing may be viewed on an IBM-PC machine running the MS-Windowsoperating system.

FIELD OF THE INVENTION

The present invention relates to human secreted proteins/polypeptides,and isolated nucleic acid molecules encoding said proteins/polypeptides,useful for detecting, preventing, diagnosing, prognosticating, treating,and/or ameliorating diseases and disorders related to saidproteins/polypeptides (relatedness may be by direct or indirectassociation, by cause, by consequence, or by effect on said diseases anddisorders). Antibodies that bind these polypeptides are also encompassedby the present invention. Also encompassed by the invention are vectors,host cells, and recombinant and synthetic methods for producing saidpolynucleotides, polypeptides, and/or antibodies. The invention furtherencompasses screening methods for identifying agonists and antagonistsof polynucleotides and polypeptides of the invention. The presentinvention further encompasses methods and compositions for inhibiting orenhancing the production and function of the polypeptides of the presentinvention.

BACKGROUND OF THE INVENTION

Unlike bacterium, which exist as a single compartment surrounded by amembrane, human cells and other eukaryotes are subdivided by membranesinto many functionally distinct compartments. Each membrane-boundedcompartment, or organelle, contains different proteins essential for thefunction of the organelle. The cell uses “sorting signals,” which areamino acid motifs located within the protein, to target proteins toparticular cellular organelles.

One type of sorting signal, called a signal sequence, a signal peptide,or a leader sequence, directs a class of proteins to an organelle calledthe endoplasmic reticulum (ER). The ER separates the membrane-boundedproteins from all other types of proteins. Once localized to the ER,both groups of proteins can be further directed to another organellecalled the Golgi apparatus. Here, the Golgi distributes the proteins tovesicles, including secretory vesicles, the cell membrane, lysosomes,and the other organelles.

Proteins targeted to the ER by a signal sequence can be released intothe extracellular space as a secreted protein. For example, vesiclescontaining secreted proteins can fuse with the cell membrane and releasetheir contents into the extracellular space—a process called exocytosis.Exocytosis can occur constitutively or after receipt of a triggeringsignal. In the latter case, the proteins are stored in secretoryvesicles (or secretory granules) until exocytosis is triggered.Similarly, proteins residing on the cell membrane can also be secretedinto the extracellular space by proteolytic cleavage of a “linker”holding the protein to the membrane.

Thus there exists a clear need for identifying and using novel secretedpolynucleotides and polypeptides. Identification and sequencing of humangenes is a major goal of modern scientific research. For example, byidentifying genes and determining their sequences, scientists have beenable to make large quantities of valuable human “gene products.” Theseinclude human insulin, interferon, Factor VIII, tumor necrosis factor,human growth hormone, tissue plasminogen activator, and numerous othercompounds. Additionally, knowledge of gene sequences can provide the keyto treatment or cure of genetic diseases (such as muscular dystrophy andcystic fibrosis).

SUMMARY OF THE INVENTION

The present invention relates to human secreted proteins/polypeptides,and isolated nucleic acid molecules encoding said proteins/polypeptides,useful for detecting, preventing, diagnosing, prognosticating, treating,and/or ameliorating diseases and disorders related to saidproteins/polypeptides (relatedness may be by direct or indirectassociation, or by cause, consequence, or effect on said diseases anddisorders). Antibodies that bind these polypeptides are also encompassedby the present invention. Also encompassed by the invention are vectors,host cells, and recombinant and synthetic methods for producing saidpolynucleotides, polypeptides, and/or antibodies. The invention furtherencompasses screening methods for identifying agonists and antagonistsof polynucleotides and polypeptides of the invention. The presentinvention further encompasses methods and compositions for inhibiting orenhancing the production and function of the polypeptides of the presentinvention.

DETAILED DESCRIPTION

Polynucleotides and Polypeptides of the Invention

Description of Table 1A

Table 1A summarizes information concerning certain polynucleotides andpolypeptides of the invention. The first column provides the gene numberin the application for each clone identifier. The second column providesa unique clone identifier, “Clone ID:”, for a cDNA clone related to eachcontig sequence disclosed in Table 1A. Third column, the cDNA Clonesidentified in the second column were deposited as indicated in the thirdcolumn (i.e. by ATCC Deposit No: Z and deposit date). Some of thedeposits contain multiple different clones corresponding to the samegene. In the fourth column, “Vector” refers to the type of vectorcontained in the corresponding cDNA Clone identified in the secondcolumn. In the fifth column, the nucleotide sequence identified as “NTSEQ ID NO:X” was assembled from partially homologous (“overlapping”)sequences obtained from the corresponding cDNA clone identified in thesecond column and, in some cases, from additional related cDNA clones.The overlapping sequences were assembled into a single contiguoussequence of high redundancy (usually three to five overlapping sequencesat each nucleotide position), resulting in a final sequence identifiedas SEQ ID NO:X. In the sixth column, “Total NT Seq.” refers to the totalnumber of nucleotides in the contig sequence identified as SEQ ID NO:X.”The deposited clone may contain all or most of these sequences,reflected by the nucleotide position indicated as “5′ NT of Clone Seq.”(seventh column) and the “3′ NT of Clone Seq.” (eighth column) of SEQ IDNO:X. In the ninth column, the nucleotide position of SEQ ID NO:X of theputative start codon (methionine) is identified as “5′ NT of StartCodon.” Similarly, in column ten, the nucleotide position of SEQ ID NO:Xof the predicted signal sequence is identified as “5′ NT of First AA ofSignal Pep.” In the eleventh column, the translated amino acid sequence,beginning with the methionine, is identified as “AA SEQ ID NO:Y,”although other reading frames can also be routinely translated usingknown molecular biology techniques. The polypeptides produced by thesealternative open reading frames are specifically contemplated by thepresent invention.

In the twelfth and thirteenth columns of Table 1A, the first and lastamino acid position of SEQ ID NO:Y of the predicted signal peptide isidentified as “First AA of Sig Pep” and “Last AA of Sig Pep.” In thefourteenth column, the predicted first amino acid position of SEQ IDNO:Y of the secreted portion is identified as “Predicted First AA ofSecreted Portion”. The amino acid position of SEQ ID NO:Y of the lastamino acid encoded by the open reading frame is identified in thefifteenth column as “Last AA of ORF”.

SEQ ID NO:X (where X may be any of the polynucleotide sequencesdisclosed in the sequence listing) and the translated SEQ ID NO:Y (whereY may be any of the polypeptide sequences disclosed in the sequencelisting) are sufficiently accurate and otherwise suitable for a varietyof uses well known in the art and described further below. For instance,SEQ ID NO:X is useful for designing nucleic acid hybridization probesthat will detect nucleic acid sequences contained in SEQ ID NO:X or thecDNA contained in the deposited clone. These probes will also hybridizeto nucleic acid molecules in biological samples, thereby enabling avariety of forensic and diagnostic methods of the invention. Similarly,polypeptides identified from SEQ ID NO:Y may be used, for example, togenerate antibodies which bind specifically to proteins containing thepolypeptides and the secreted proteins encoded by the cDNA clonesidentified in Table 1A and/or elsewhere herein

Nevertheless, DNA sequences generated by sequencing reactions cancontain sequencing errors. The errors exist as misidentifiednucleotides, or as insertions or deletions of nucleotides in thegenerated DNA sequence. The erroneously inserted or deleted nucleotidescause frame shifts in the reading frames of the predicted amino acidsequence. In these cases, the predicted amino acid sequence divergesfrom the actual amino acid sequence, even though the generated DNAsequence may be greater than 99.9% identical to the actual DNA sequence(for example, one base insertion or deletion in an open reading frame ofover 1000 bases).

Accordingly, for those applications requiring precision in thenucleotide sequence or the amino acid sequence, the present inventionprovides not only the generated nucleotide sequence identified as SEQ IDNO:X, and the predicted translated amino acid sequence identified as SEQID NO:Y, but also a sample of plasmid DNA containing a human cDNA of theinvention deposited with the ATCC, as set forth in Table 1A. Thenucleotide sequence of each deposited plasmid can readily be determinedby sequencing the deposited plasmid in accordance with known methods

The predicted amino acid sequence can then be verified from suchdeposits. Moreover, the amino acid sequence of the protein encoded by aparticular plasmid can also be directly determined by peptide sequencingor by expressing the protein in a suitable host cell containing thedeposited human cDNA, collecting the protein, and determining itssequence.

Also provided in Table 1A is the name of the vector which contains thecDNA plasmid. Each vector is routinely used in the art. The followingadditional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Phagemid pBS may be excised fromthe Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excisedfrom the Zap Express vector. Both phagemids may be transformed into E.coli strain XL-1 Blue, also available from Stratagene

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, wereobtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md.20897. All Sport vectors contain an ampicillin resistance gene and maybe transformed into E. coli strain DH10B, also available from LifeTechnologies. See, for instance, Gruber, C. E., et al., Focus 15:59(1993). Vector lafmid BA (Bento Soares, Columbia University, New York,N.Y.) contains an ampicillin resistance gene and can be transformed intoE. coli strain XL-1 Blue. Vector pCR®2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ IDNO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID). Thecorresponding gene can be isolated in accordance with known methodsusing the sequence information disclosed herein. Such methods include,but are not limited to, preparing probes or primers from the disclosedsequence and identifying or amplifying the corresponding gene fromappropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs,and/or species homologs. Procedures known in the art can be used toobtain full-length genes, allelic variants, splice variants, full-lengthcoding portions, orthologs, and/or species homologs of genescorresponding to SEQ ID NO:X and SEQ ID NO:Y using information from thesequences disclosed herein or the clones deposited with the ATCC. Forexample, allelic variants and/or species homologs may be isolated andidentified by making suitable probes or primers from the sequencesprovided herein and screening a suitable nucleic acid source for allelicvariants and/or the desired homologue.

The present invention provides a polynucleotide comprising, oralternatively consisting of, the nucleic acid sequence of SEQ ID NO:Xand/or a cDNA contained in ATCC Deposit No. Z. The present inventionalso provides a polypeptide comprising, or alternatively, consisting of,the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ IDNO:X, and/or a polypeptide encoded by a cDNA contained in ATCC depositNo. Z. Polynucleotides encoding a polypeptide comprising, oralternatively consisting of the polypeptide sequence of SEQ ID NO:Y, apolypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by thecDNA contained in ATCC Deposit No. Z, are also encompassed by theinvention. The present invention further encompasses a polynucleotidecomprising, or alternatively consisting of the complement of the nucleicacid sequence of SEQ ID NO:X, and/or the complement of the coding strandof the cDNA contained in ATCC Deposit No. Z.

Description of Table 1B (Comprised of Tables 1B.1 and 1B.2)

Table 1B.1 and Table 1B.2 summarize some of the polynucleotidesencompassed by the invention (including cDNA clones related to thesequences (Clone ID:), contig sequences (contig identifier (Contig ID:)and contig nucleotide sequence identifiers (SEQ ID NO:X)) and furthersummarizes certain characteristics of these polynucleotides and thepolypeptides encoded thereby. The first column of Tables 1B.1 and 1B.2provide the gene numbers in the application for each clone identifier.The second column of Tables 1B.1 and 1B.2 provide unique cloneidentifiers, “Clone ID:”, for cDNA clones related to each contigsequence disclosed in Table 1A and/or Table 1B. The third column ofTables 1B.1 and 1B.2 provide unique contig identifiers, “Contig ID:” foreach of the contig sequences disclosed in these tables. The fourthcolumn of Tables 1B.1 and 1B.2 provide the sequence identifiers, “SEQ IDNO:X”, for each of the contig sequences disclosed in Table 1A and/or 1B.

Table 1B.1

The fifth column of Table 1B.1, “ORF (From-To)”, provides the location(i.e., nucleotide position numbers) within the polynucleotide sequenceof SEQ ID NO:X that delineates the preferred open reading frame (ORF)that encodes the amino acid sequence shown in the sequence listing andreferenced in Table 1B.1 as SEQ ID NO:Y (column 6). Column 7 of Table1B.1 lists residues comprising predicted epitopes contained in thepolypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y).Identification of potential immunogenic regions was performed accordingto the method of Jameson and Wolf (CABIOS, 4; 181-186 (1988));specifically, the Genetics Computer Group (GCG) implementation of thisalgorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Packagev10.0, Genetics Computer Group (GCG), Madison, Wis.). This methodreturns a measure of the probability that a given residue is found onthe surface of the protein. Regions where the antigenic index score isgreater than 0.9 over at least 6 amino acids are indicated in Table 1B.1as “Predicted Epitopes”. In particular embodiments, polypeptides of theinvention comprise, or alternatively consist of, one, two, three, four,five or more of the predicted epitopes described in Table 1B.1. It willbe appreciated that depending on the analytical criteria used to predictantigenic determinants, the exact address of the determinant may varyslightly. Column 8 of Table 1B.1 (“Cytologic Band”) provides thechromosomal location of polynucleotides corresponding to SEQ ID NO:X.Chromosomal location was determined by finding exact matches to EST andcDNA sequences contained in the NCBI (National Center for BiotechnologyInformation) UniGene database. Given a presumptive chromosomal location,disease locus association was determined by comparison with the MorbidMap, derived from Online Mendelian Inheritance in Man (Online MendelianInheritance in Man, OMIM™. McKusick-Nathans Institute for GeneticMedicine, Johns Hopkins University (Baltimore, Md.) and National Centerfor Biotechnology Information, National Library of Medicine (Bethesda,Md.) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). Ifthe putative chromosomal location of the Query overlaps with thechromosomal location of a Morbid Map entry, an OMIM identificationnumber is disclosed in Table 1B.1, column 9 labeled “OMIM DiseaseReference(s)”. A key to the OMIM reference identification numbers isprovided in Table 5.

Table 1B.2

Column 5 of Table 1B.2, “Tissue Distribution” shows the expressionprofile of tissue, cells, and/or cell line libraries which express thepolynucleotides of the invention. The first code number shown in Table1B.2 column 5 (preceding the colon), represents the tissue/cell sourceidentifier code corresponding to the key provided in Table 4. Expressionof these polynucleotides was not observed in the other tissues and/orcell libraries tested. The second number in column 5 (following thecolon), represents the number of times a sequence corresponding to thereference polynucleotide sequence (e.g., SEQ ID NO:X) was identified inthe corresponding tissue/cell source. Those tissue/cell sourceidentifier codes in which the first two letters are “AR” designateinformation generated using DNA array technology. Utilizing thistechnology, cDNAs were amplified by PCR and then transferred, induplicate, onto the array. Gene expression was assayed throughhybridization of first strand cDNA probes to the DNA array. cDNA probeswere generated from total RNA extracted from a variety of differenttissues and cell lines. Probe synthesis was performed in the presence of³³P dCTP, using oligo(dT) to prime reverse transcription. Afterhybridization, high stringency washing conditions were employed toremove non-specific hybrids from the array. The remaining signal,emanating from each gene target, was measured using a Phosphorimager.Gene expression was reported as Phosphor Stimulating Luminescence (PSL)which reflects the level of phosphor signal generated from the probehybridized to each of the gene targets represented on the array. A localbackground signal subtraction was performed before the total signalgenerated from each array was used to normalize gene expression betweenthe different hybridizations. The value presented after “[array code]:”represents the mean of the duplicate values, following backgroundsubtraction and probe normalization. One of skill in the art couldroutinely use this information to identify normal and/or diseasedtissue(s) which show a predominant expression pattern of thecorresponding polynucleotide of the invention or to identifypolynucleotides which show predominant and/or specific tissue and/orcell expression.

Description of Table 1C

Table 1C summarizes additional polynucleotides encompassed by theinvention (including cDNA clones related to the sequences (Clone ID:),contig sequences (contig identifier (Contig ID:) contig nucleotidesequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ IDNO:B). The first column provides a unique clone identifier, “Clone ID:”,for a cDNA clone related to each contig sequence. The second columnprovides the sequence identifier, “SEQ ID NO:X”, for each contigsequence. The third column provides a unique contig identifier, “ContigID:” for each contig sequence. The fourth column, provides a BACidentifier “BAC ID NO:A” for the BAC clone referenced in thecorresponding row of the table. The fifth column provides the nucleotidesequence identifier, “SEQ ID NO:B” for a fragment of the BAC cloneidentified in column four of the corresponding row of the table. Thesixth column, “Exon From-To”, provides the location (i.e., nucleotideposition numbers) within the polynucleotide sequence of SEQ ID NO:Bwhich delineate certain polynucleotides of the invention that are alsoexemplary members of polynucleotide sequences that encode polypeptidesof the invention (e.g., polypeptides containing amino acid sequencesencoded by the polynucleotide sequences delineated in column six, andfragments and variants thereof).

Description of Table 1D

Table 1D: In preferred embodiments, the present invention encompasses amethod of detecting, preventing, treating, and/or ameliorating a diseaseor disorder listed as listed in the “Preferred Indications” column ofTable 1D (below); comprising administering to a patient (in which suchdetection, prevention, treatment, and/or amelioration is desired) aprotein, nucleic acid, or antibody of the invention (or fragment orvariant thereof) represented by Table 1A and Table 1D (in the same rowas the disease or disorder to be treated is listed in the “PreferredIndications” column of Table 1D) in an amount effective to detect,prevent, treat, or ameliorate the disease or disorder.

As indicated in Table 1D, the polynucleotides, polypeptides, agonists,or antagonists of the present invention (including antibodies) can beused in assays to test for one or more biological activities. If thesepolynucleotides and polypeptides do exhibit activity in a particularassay, it is likely that these molecules may be involved in the diseasesassociated with the biological activity. Thus, the polynucleotides orpolypeptides, or agonists or antagonists thereof (including antibodies)could be used to prevent, treat, or ameliorate the associated disease.

The present invention encompasses methods of detecting, preventing,diagnosing, prognosticating, treating, and/or ameliorating a disease ordisorder. In preferred embodiments, the present invention encompasses amethod of detecting, diagnosing, treating, preventing, or ameliorating adisease or disorder listed in the “Preferred Indications” column ofTable 1D; comprising administering to a patient in which such treatment,prevention, or amelioration is desired a protein, nucleic acid, orantibody of the invention (or fragment or variant thereof) in an amounteffective to treat, prevent, or ameliorate the disease or disorder. Thefirst and seccond columns of Table 1D show the “Gene No.” and “cDNAClone ID No.”, respectively, indicating certain nucleic acids andproteins (or antibodies against the same) of the invention (includingpolynucleotide, polypeptide, and antibody fragments or variants thereof)that may be used in detecting, preventing, diagnosing, prognosticating,treating, and/or ameliorating the disease(s) or disorder(s) indicated inthe corresponding row in Column 3 of Table 1D.

In another embodiment, the present invention also encompasses methods ofpreventing, treating, diagnosing, or ameliorating a disease or disorderlisted in the “Preferred Indications” column of Table 1D; comprisingadministering to a patient combinations of the proteins, nucleic acids,or antibodies of the invention (or fragments or variants thereof),sharing similar indications as shown in the corresponding rows in Column3 of Table 1D.

The “Preferred Indication” column describes diseases, disorders, and/orconditions that may be treated, prevented, diagnosed, or ameliorated bya protein, nucleic acid, or antibody of the invention (or fragment orvariant thereof).

The recitation of “Cancer” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof) maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g.,leukemias, cancers, and/or as described below under “HyperproliferativeDisorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cancer” recitationin the “Preferred Indication” column of Table 1D may be used forexample, to diagnose, treat, prevent, and/or ameliorate a neoplasmlocated in a tissue selected from the group consisting of: colon,abdomen, bone, breast, digestive system, liver, pancreas, prostate,peritoneum, lung, blood (e.g., leukemia), endocrine glands (adrenal,parathyroid, pituitary, testicles, ovary, thymus, thyroid), uterus, eye,head and neck, nervous (central and peripheral), lymphatic system,pelvic, skin, soft tissue, spleen, thoracic, and urogenital.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cancer” recitationin the “Preferred Indication” column of Table 1D, may be used forexample, to diagnose, treat, prevent, and/or ameliorate a pre-neoplasticcondition, selected from the group consisting of: hyperplasia (e.g.,endometrial hyperplasia and/or as described in the section entitled“Hyperproliferative Disorders”), metaplasia (e.g., connective tissuemetaplasia, atypical metaplasia, and/or as described in the sectionentitled “Hyperproliferative Disorders”), and/or dysplasia (e.g.,cervical dysplasia, and bronchopulmonary dysplasia).

In another specific embodiment, a protein, nucleic acid, or antibody ofthe invention (or fragment or variant thereof) having a “Cancer”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a benigndysproliferative disorder selected from the group consisting of: benigntumors, fibrocystic conditions, tissue hypertrophy, and/or as describedin the section entitled “Hyperproliferative Disorders”.

The recitation of “Immune/Hematopoietic” in the “Preferred Indication”column indicates that the corresponding nucleic acid and protein, orantibody against the same, of the invention (or fragment or variantthereof), may be used for example, to diagnose, treat, prevent, and/orameliorate diseases and/or disorders relating to neoplastic diseases(e.g., as described below under “Hyperproliferative Disorders”), blooddisorders (e.g., as described below under “Immune Activity”“Cardiovascular Disorders” and/or “Blood-Related Disorders”), andinfections (e.g., as described below under “Infectious Disease”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having the“Immune/Hematopoietic” recitation in the “Preferred Indication” columnof Table 1D, may be used for example, to diagnose, treat, prevent,and/or ameliorate a disease or disorder selected from the groupconsisting of: anemia, pancytopenia, leukopenia, thrombocytopenia,leukemias, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocyticanemia (ALL), plasmacytomas, multiple myeloma, Burkitt's lymphoma,arthritis, asthma, AIDS, autoimmune disease, rheumatoid arthritis,granulomatous disease, immune deficiency, inflammatory bowel disease,sepsis, neutropenia, neutrophilia, psoriasis, immune reactions totransplanted organs and tissues, systemic lupus erythematosis,hemophilia, hypercoagulation, diabetes mellitus, endocarditis,meningitis, Lyme Disease, and allergies.

The recitation of “Reproductive” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe reproductive system (e.g., as described below under “ReproductiveSystem Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Reproductive”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cryptorchism,prostatitis, inguinal hernia, varicocele, leydig cell tumors, verrucouscarcinoma, prostatitis, malacoplakia, Peyronie's disease, penilecarcinoma, squamous cell hyperplasia, dysmenorrhea, ovarianadenocarcinoma, Turner's syndrome, mucopurulent cervicitis,Sertoli-leydig tumors, ovarian cancer, uterine cancer, pelvicinflammatory disease, testicular cancer, prostate cancer, Klinefelter'ssyndrome, Young's syndrome, premature ejaculation, diabetes mellitus,cystic fibrosis, Kartagener's syndrome, testicular atrophy, testicularfeminization, anorchia, ectopic testis, epididymitis, orchitis,gonorrhea, syphilis, testicular torsion, vasitis nodosa, germ celltumors, stromal tumors, dysmenorrhea, retroverted uterus, endometriosis,fibroids, adenomyosis, anovulatory bleeding, amenorrhea, Cushing'ssyndrome, hydatidiform moles, Asherman's syndrome, premature menopause,precocious puberty, uterine polyps, dysfunctional uterine bleeding,cervicitis, chronic cervicitis, mucopurulent cervicitis, cervicaldysplasia, cervical polyps, Nabothian cysts, cervical erosion, cervicalincompetence, cervical neoplasms, pseudohermaphroditism, andpremenstrual syndrome.

The recitation of “Musculoskeletal” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe immune system (e.g., as described below under “Immune Activity”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Musculoskeletal”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: bone cancers (e.g.,osteochondromas, benign chondromas, chondroblastoma, chondromyxoidfibromas, osteoid osteomas, giant cell tumors, multiple myeloma,osteosarcomas), Paget's Disease, rheumatoid arthritis, systemic lupuserythematosus, osteomyelitis, Lyme Disease, gout, bursitis, tendonitis,osteoporosis, osteoarthritis, muscular dystrophy, mitochondrialmyopathy, cachexia, and multiple sclerosis.

The recitation of “Cardiovascular” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe cardiovascular system (e.g., as described below under“Cardiovascular Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cardiovascular”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: myxomas, fibromas,rhabdomyomas, cardiovascular abnormalities (e.g., congenital heartdefects, cerebral arteriovenous malformations, septal defects), heartdisease (e.g., heart failure, congestive heart disease, arrhythmia,tachycardia, fibrillation, pericardial Disease, endocarditis), cardiacarrest, heart valve disease (e.g., stenosis, regurgitation, prolapse),vascular disease (e.g., hypertension, coronary artery disease, angina,aneurysm, arteriosclerosis, peripheral vascular disease), hyponatremia,hypematremia, hypokalemia, and hyperkalemia.

The recitation of “Mixed Fetal” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Mixed Fetal”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: spina bifida,hydranencephaly, neurofibromatosis, fetal alcohol syndrome, diabetesmellitus, PKU, Down's syndrome, Patau syndrome, Edwards syndrome, Turnersyndrome, Apert syndrome, Carpenter syndrome, Conradi syndrome, Crouzonsyndrome, cutis laxa, Cornelia de Lange syndrome, Ellis-van Creveldsyndrome, Holt-Oram syndrome, Kartagener syndrome, Meckel-Grubersyndrome, Noonan syndrome, Pallister-Hall syndrome, Rubinstein-Taybisyndrome, Scimitar syndrome, Smith-Lemli-Opitz syndrome,thromocytopenia-absent radius (TAR) syndrome, Treacher Collins syndrome,Williams syndrome, Hirschsprung's disease, Meckel's diverticulum,polycystic kidney disease, Turner's syndrome, and gonadal dysgenesis,Klippel-Feil syndrome, Ostogenesis imperfecta, muscular dystrophy,Tay-Sachs disease, Wilm's tumor, neuroblastoma, and retinoblastoma.

The recitation of “Excretory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and renaldisorders (e.g., as described below under “Renal Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Excretory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: bladder cancer, prostatecancer, benign prostatic hyperplasia, bladder disorders (e.g., urinaryincontinence, urinary retention, urinary obstruction, urinary tractInfections, interstitial cystitis, prostatitis, neurogenic bladder,hematuria), renal disorders (e.g., hydronephrosis, proteinuria, renalfailure, pyelonephritis, urolithiasis, reflux nephropathy, andunilateral obstructive uropathy).

The recitation of “Neural/Sensory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the nervous system (e.g., as described below under “NeuralActivity and Neurological Diseases”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Neural/Sensory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: brain cancer (e.g.,brain stem glioma, brain tumors, central nervous system (Primary)lymphoma, central nervous system lymphoma, cerebellar astrocytoma, andcerebral astrocytoma, neurodegenerative disorders (e.g., Alzheimer'sDisease, Creutzfeldt-Jakob Disease, Parkinson's Disease, and IdiopathicPresenile Dementia), encephalomyelitis, cerebral malaria, meningitis,metabolic brain diseases (e.g., phenylketonuria and pyruvate carboxylasedeficiency), cerebellar ataxia, ataxia telangiectasia, and AIDS DementiaComplex, schizophrenia, attention deficit disorder, hyperactiveattention deficit disorder, autism, and obsessive compulsive disorders.

The recitation of “Respiratory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the respiratory system (e.g., as described below under“Respiratory Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Respiratory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cancers of therespiratory system such as larynx cancer, pharynx cancer, tracheacancer, epiglottis cancer, lung cancer, squamous cell carcinomas, smallcell (oat cell) carcinomas, large cell carcinomas, and adenocarcinomas.Allergic reactions, cystic fibrosis, sarcoidosis, histiocytosis X,infiltrative lung diseases (e.g., pulmonary fibrosis and lymphoidinterstitial pneumonia), obstructive airway diseases (e.g., asthma,emphysema, chronic or acute bronchitis), occupational lung diseases(e.g., silicosis and asbestosis), pneumonia, and pleurisy.

The recitation of “Endocrine” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the respiratory system (e.g., as described below under“Respiratory Disorders”), renal disorders (e.g., as described belowunder “Renal Disorders”), and disorders of the endocrine system (e.g.,as described below under “Endocrine Disorders”.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having an “Endocrine”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cancers of endocrinetissues and organs (e.g., cancers of the hypothalamus, pituitary gland,thyroid gland, parathyroid glands, pancreas, adrenal glands, ovaries,and testes), diabetes (e.g., diabetes insipidus, type I and type IIdiabetes mellitus), obesity, disorders related to pituitary glands(e.g., hyperpituitarism, hypopituitarism, and pituitary dwarfism),hypothyroidism, hyperthyroidism, goiter, reproductive disorders (e.g.male and female infertility), disorders related to adrenal glands (e.g.,Addison's Disease, corticosteroid deficiency, and Cushing's Syndrome),kidney cancer (e.g., hypemephroma, transitional cell cancer, and Wilm'stumor), diabetic nephropathy, interstitial nephritis, polycystic kidneydisease, glomerulonephritis (e.g., IgM mesangial proliferativeglomerulonephritis and glomerulonephritis caused by autoimmunedisorders; such as Goodpasture's syndrome), and nephrocalcinosis.

The recitation of “Digestive” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the gastrointestinal system (e.g., as described below under“Gastrointestinal Disorders”.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Digestive”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: ulcerative colitis,appendicitis, Crohn's disease, hepatitis, hepatic encephalopathy, portalhypertension, cholelithiasis, cancer of the digestive system (e.g.,biliary tract cancer, stomach cancer, colon cancer, gastric cancer,pancreatic cancer, cancer of the bile duct, tumors of the colon (e.g.,polyps or cancers), and cirrhosis), pancreatitis, ulcerative disease,pyloric stenosis, gastroenteritis, gastritis, gastric atropy, benigntumors of the duodenum, distension, irritable bowel syndrome,malabsorption, congenital disorders of the small intestine, bacterialand parasitic infection, megacolon, Hirschsprung's disease, aganglionicmegacolon, acquired megacolon, colitis, anorectal disorders (e.g., analfistulas, hemorrhoids), congenital disorders of the liver (e.g.,Wilson's disease, hemochromatosis, cystic fibrosis, biliary atresia, andalpha1-antitrypsin deficiency), portal hypertension, cholelithiasis, andjaundice.

The recitation of “Connective/Epithelial” in the “Preferred Indication”column indicates that the corresponding nucleic acid and protein, orantibody against the same, of the invention (or fragment or variantthereof), may be used for example, to diagnose, treat, prevent, and/orameliorate diseases and/or disorders relating to neoplastic diseases(e.g., as described below under “Hyperproliferative Disorders”),cellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), angiogenesis (e.g., as describedbelow under “Anti-Angiogenesis Activity”), and or to promote or inhibitregeneration (e.g., as described below under “Regeneration”), and woundhealing (e.g., as described below under “Wound Healing and EpithelialCell Proliferation”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a“Connective/Epithelial” recitation in the “Preferred Indication” columnof Table 1D, may be used for example, to diagnose, treat, prevent,and/or ameliorate a disease or disorder selected from the groupconsisting of: connective tissue metaplasia, mixed connective tissuedisease, focal epithelial hyperplasia, epithelial metaplasia,mucoepithelial dysplasia, graft v. host disease, polymyositis, cystichyperplasia, cerebral dysplasia, tissue hypertrophy, Alzheimer'sdisease, lymphoproliferative disorder, Waldenstron's macroglobulinemia,Crohn's disease, pernicious anemia, idiopathic Addison's disease,glomerulonephritis, bullous pemphigoid, Sjogren's syndrome, diabetesmellitus, cystic fibrosis, osteoblastoma, osteoclastoma, osteosarcoma,chondrosarcoma, osteoporosis, osteocarthritis, periodontal disease,wound healing, relapsing polychondritis, vasculitis, polyarteritisnodosa, Wegener's granulomatosis, cellulitis, rheumatoid arthritis,psoriatic arthritis, discoid lupus erythematosus, systemic lupuserythematosus, scleroderma, CREST syndrome, Sjogren's syndrome,polymyositis, dermatomyositis, mixed connective tissue disease,relapsing polychondritis, vasculitis, Henoch-Schonlein syndrome,erythema nodosum, polyarteritis nodosa, temporal (giant cell) arteritis,Takayasu's arteritis, Wegener's granulomatosis, Reiter's syndrome,Behcet's syndrome, ankylosing spondylitis, cellulitis, keloids, EhlerDanlos syndrome, Marfan syndrome, pseudoxantoma elasticum, osteogeneseimperfecta, chondrodysplasias, epidermolysis bullosa, Alport syndrome,and cutis laxa.

Description of Table 1E

Table 1E provides information related to biological activities andpreferred indications for polynucleotides and polypeptides of theinvention (including antibodies, agonists, and/or antagonists thereof).Table 1E also provides information related to assays which may be usedto test polynucleotides and polypeptides of the invention (includingantibodies, agonists, and/or antagonists thereof) for the correspondingbiological activities. The first column (“Gene No.”) provides the genenumber in the application for each clone identifier. The second column(“cDNA Clone ID:”) provides the unique clone identifier for each cloneas previously described and indicated in Tables 1A, 1B, 1C, and 1D. Thethird column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ IDNumber for polypeptide sequences encoded by the corresponding cDNAclones (also as indicated in Tables 1A, 1B, and 2). The fourth column(“Biological Activity”) indicates a biological activity corresponding tothe indicated polypeptides (or polynucleotides encoding saidpolypeptides). The fifth column (“Exemplary Activity Assay”) furtherdescribes the corresponding biological activity and provides informationpertaining to the various types of assays which may be performed totest, demonstrate, or quantify the corresponding biological activity.The sixth column (“Preferred Indications”) describes particularembodiments of the invention and indications (e.g. pathologies,diseases, disorders, abnormalities, etc.) for which polynucleotides andpolypeptides of the invention (including antibodies, agonists, and/orantagonists thereof) may be used in detecting, preventing, diagnosing,prognosticating, treating, and/or ameliorating.

Table 1E describes the use of FMAT technology, inter alia, for testingor demonstrating various biological activities. Fluorometric microvolumeassay technology (FMAT) is a fluorescence-based system which provides ameans to perform nonradioactive cell- and bead-based assays to detectactivation of cell signal transduction pathways. This technology wasdesigned specifically for ligand binding and immunological assays. Usingthis technology, fluorescent cells or beads at the bottom of the wellare detected as localized areas of concentrated fluorescence using adata processing system. Unbound flurophore comprising the backgroundsignal is ignored, allowing for a wide variety of homogeneous assays.FMAT technology may be used for peptide ligand binding assays,immunofluorescence, apoptosis, cytotoxicity, and bead-basedimmunocapture assays. See, Miraglia S et. al., “Homogeneous cell andbead based assays for highthroughput screening using flourometricmicrovolume assay technology,” Journal of Biomolecular Screening;4:193-204 (1999). In particular, FMAT technology may be used to test,confirm, and/or identify the ability of polypeptides (includingpolypeptide fragments and variants) to activate signal transductionpathways. For example, FMAT technology may be used to test, confirm,and/or identify the ability of polypeptides to upregulate production ofimmunomodulatory proteins (such as, for example, interleukins, GM-CSF,Rantes, and Tumor Necrosis factors, as well as other cellular regulators(e.g. insulin)).

Table 1E also describes the use of kinase assays for testing,demonstrating, or quantifying biological activity. In this regard, thephosphorylation and de-phosphorylation of specific amino acid residues(e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteinsprovides a fast, reversible means for activation and de-activation ofcellular signal transduction pathways. Moreover, cell signaltransduction via phosphorylation/de-phosphorylation is crucial to theregulation of a wide variety of cellular processes (e.g. proliferation,differentiation, migration, apoptosis, etc.). Accordingly, kinase assaysprovide a powerful tool useful for testing, confirming, and/oridentifying polypeptides (including polypeptide fragments and variants)that mediate cell signal transduction events via proteinphosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R.“Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38Kinase Activities” Biol. Chem. 379(8-9): 1101-1110 (1998).

Description of Table 1F

Polynucleotides encoding polypeptides of the present invention can beused in assays to test for one or more biological activities. One suchbiological activity which may be tested includes the ability ofpolynucleotides and polypeptides of the invention to stimulateup-regulation or down-regulation of expression of particular genes andproteins. Hence, if polynucleotides and polypeptides of the presentinvention exhibit activity in altering particular gene and proteinexpression patterns, it is likely that these polynucleotides andpolypeptides of the present invention may be involved in, or capable ofeffecting changes in, diseases associated with the altered gene andprotein expression profiles. Hence, polynucleotides, polypeptides, orantibodies of the present invention could be used to treat saidassociated diseases.

TaqMan® assays may be performed to assess the ability of polynucleotides(and polypeptides they encode) to alter the expression pattern ofparticular “target” genes. TaqMan® reactions are performed to evaluatethe ability of a test agent to induce or repress expression of specificgenes in different cell types. TaqMan® gene expression quantificationassays (“TaqMan® assays”) are well known to, and routinely performed by,those of ordinary skill in the art. TaqMan® assays are performed in atwo step reverse transcription/polymerase chain reaction (RT-PCR). Inthe first (RT) step, cDNA is reverse transcribed from total RNA samplesusing random hexamer primers. In the second (PCR) step, PCR products aresynthesized from the cDNA using gene specific primers.

To quantify gene expression the Taqman® PCR reaction exploits the 5′nuclease activity of AmpliTaq Gold® DNA Polymerase to cleave a Taqman®probe (distinct from the primers) during PCR. The Taqman® probe containsa reporter dye at the 5′-end of the probe and a quencher dye at the 3′end of the probe. When the probe is intact, the proximity of thereporter dye to the quencher dye results in suppression of the reporterfluorescence. During PCR, if the target of interest is present, theprobe specifically anneals between the forward and reverse primer sites.AmpliTaq Fold DNA Polymerase then cleaves the probe between the reporterand quencher when the probe hybridizes to the target, resulting inincreased fluorescence of the reporter (see FIG. 2). Accumulation of PCRproducts is detected directly by monitoring the increase in fluorescenceof the reporter dye.

After the probe fragments are displaced from the target, polymerizationof the strand continues. The 3′-end of the probe is blocked to preventextension of the probe during PCR. This process occurs in every cycleand does not interfere with the exponential accumulation of product. Theincrease in fluorescence signal is detected only if the target sequenceis complementary to the probe and is amplified during PCR. Because ofthese requirements, any nonspecific amplification is not detected.

For test sample preparation, vector controls or constructs containingthe coding sequence for the gene of interest are transfected into cells,such as for example 293T cells, and supernatants collected after 48hours. For cell treatment and RNA isolation, multiple primary humancells or human cell lines are used; such cells may include but are notlimited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, HumanUmbilical Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, andTHP-1 cell lines. Cells are plated in growth media and growth isarrested by culturing without media change for 3 days, or by switchingcells to low serum media and incubating overnight. Cells are treated for1, 6, or 24 hours with either vector control supernatant or samplesupernatant (or purified/partially purified protein preparations inbuffer). Total RNA is isolated; for example, by using Trizol extractionor by using the Ambion RNAqueous™-4PCR RNA isolation system. Expressionlevels of multiple genes are analyzed using Taqman®, and expression inthe test sample is compared to control vector samples to identify genesinduced or repressed. Each of the above described techniques are wellknown to, and routinely performed by, those of ordinary skill in theart.

Table 1F indicates particular disease classes and preferred indicationsfor which polynucleotides, polypeptides, or antibodies of the presentinvention may be used in detecting, diagnosing, preventing, treatingand/or ameliorating said diseases and disorders based on “target” geneexpression patterns which may be up- or down-regulated bypolynucleotides (and the encoded polypeptides) corresponding to eachindicated cDNA Clone ID (shown in Table 1F, Column 2).

Thus, in preferred embodiments, the present invention encompasses amethod of detecting, diagnosing, preventing, treating, and/orameliorating a disease or disorder listed in the “Disease Class” and/or“Preferred Indication” columns of Table 1F; comprising administering toa patient in which such detection, diagnosis, prevention, or treatmentis desired a protein, nucleic acid, or antibody of the invention (orfragment or variant thereof) in an amount effective to detect, diagnose,prevent, treat, or ameliorate the disease or disorder. The first andsecond columns of Table 1D show the “Gene No.” and “cDNA Clone ID No.”,respectively, indicating certain nucleic acids and proteins (orantibodies against the same) of the invention (including polynucleotide,polypeptide, and antibody fragments or variants thereof) that may beused in detecting, diagnosing, preventing, treating, or ameliorating thedisease(s) or disorder(s) indicated in the corresponding row in the“Disease Class” or “Preferred Indication” Columns of Table 1F.

In another embodiment, the present invention also encompasses methods ofdetecting, diagnosing, preventing, treating, or ameliorating a diseaseor disorder listed in the “Disease Class” or “Preferred Indication”Columns of Table 1F; comprising administering to a patient combinationsof the proteins, nucleic acids, or antibodies of the invention (orfragments or variants thereof), sharing similar indications as shown inthe corresponding rows in the “Disease Class” or “Preferred Indication”Columns of Table 1F.

The “Disease Class” Column of Table 1F provides a categorizeddescriptive heading for diseases, disorders, and/or conditions (morefully described below) that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Preferred Indication” Column of Table 1F describes diseases,disorders, and/or conditions that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Cell Line” and “Exemplary Targets” Columns of Table 1F indicateparticular cell lines and target genes, respectively, which may showaltered gene expression patterns (i.e., up- or down-regulation of theindicated target gene) in Taqman® assays, performed as described above,utilizing polynucleotides of the cDNA Clone ID shown in thecorresponding row. Alteration of expression patterns of the indicated“Exemplary Target” genes is correlated with a particular “Disease Class”and/or “Preferred Indication” as shown in the corresponding row underthe respective column headings.

The “Exemplary Accessions” Column indicates GenBank Accessions(available online through the National Center for BiotechnologyInformation (NCBI) at http://www.ncbi.nlm.nih.gov/) which correspond tothe “Exemplary Targets” shown in the adjacent row.

The recitation of “Cancer” in the “Disease Class” Column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof) may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorateneoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., asdescribed below under “Hyperproliferative Disorders”).

The recitation of “Immune” in the “Disease Class” column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), blood disorders (e.g., asdescribed below under “Immune Activity” “Cardiovascular Disorders”and/or “Blood-Related Disorders”), and infections (e.g., as describedbelow under “Infectious Disease”).

The recitation of “Angiogenesis” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), diseases and/or disordersof the cardiovascular system (e.g., as described below under“Cardiovascular Disorders”), diseases and/or disorders involvingcellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), diseases and/or disorders involvingangiogenesis (e.g., as described below under “Anti-AngiogenesisActivity”), to promote or inhibit cell or tissue regeneration (e.g., asdescribed below under “Regeneration”), or to promote wound healing(e.g., as described below under “Wound Healing and Epithelial CellProliferation”).

The recitation of “Diabetes” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diabetes(including diabetes mellitus types I and II), as well as diseases and/ordisorders associated with, or consequential to, diabetes (e.g. asdescribed below under “Endocrine Disorders,” “Renal Disorders,” and“Gastrointestinal Disorders”).

Description of Table 1F

Polynucleotides encoding polypeptides of the present invention can beused in assays to test for one or more biological activities. One suchbiological activity which may be tested includes the ability ofpolynucleotides and polypeptides of the invention to stimulateup-regulation or down-regulation of expression of particular genes andproteins. Hence, if polynucleotides and polypeptides of the presentinvention exhibit activity in altering particular gene and proteinexpression patterns, it is likely that these polynucleotides andpolypeptides of the present invention may be involved in, or capable ofeffecting changes in, diseases associated with the altered gene andprotein expression profiles. Hence, polynucleotides, polypeptides, orantibodies of the present invention could be used to treat saidassociated diseases.

TaqMan® assays may be performed to assess the ability of polynucleotides(and polypeptides they encode) to alter the expression pattern ofparticular “target” genes. TaqMan® reactions are performed to evaluatethe ability of a test agent to induce or repress expression of specificgenes in different cell types. TaqMan® gene expression quantificationassays (“TaqMan® assays”) are well known to, and routinely performed by,those of ordinary skill in the art. TaqMan® assays are performed in atwo step reverse transcription/polymerase chain reaction (RT-PCR). Inthe first (RT) step, cDNA is reverse transcribed from total RNA samplesusing random hexamer primers. In the second (PCR) step, PCR products aresynthesized from the cDNA using gene specific primers.

To quantify gene expression the Taqman® PCR reaction exploits the 5′nuclease activity of AmpliTaq Gold® DNA Polymerase to cleave a Taqman®probe (distinct from the primers) during PCR. The Taqman® probe containsa reporter dye at the 5′-end of the probe and a quencher dye at the 3′end of the probe. When the probe is intact, the proximity of thereporter dye to the quencher dye results in suppression of the reporterfluorescence. During PCR, if the target of interest is present, theprobe specifically anneals between the forward and reverse primer sites.AmpliTaq Fold DNA Polymerase then cleaves the probe between the reporterand quencher when the probe hybridizes to the target, resulting inincreased fluorescence of the reporter (see FIG. 2). Accumulation of PCRproducts is detected directly by monitoring the increase in fluorescenceof the reporter dye.

After the probe fragments are displaced from the target, polymerizationof the strand continues. The 3′-end of the probe is blocked to preventextension of the probe during PCR. This process occurs in every cycleand does not interfere with the exponential accumulation of product. Theincrease in fluorescence signal is detected only if the target sequenceis complementary to the probe and is amplified during PCR. Because ofthese requirements, any nonspecific amplification is not detected.

For test sample preparation, vector controls or constructs containingthe coding sequence for the gene of interest are transfected into cells,such as for example 293T cells, and supernatants collected after 48hours. For cell treatment and RNA isolation, multiple primary humancells or human cell lines are used; such cells may include but are notlimited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, HumanUmbilical Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, andTHP-1 cell lines. Cells are plated in growth media and growth isarrested by culturing without media change for 3 days, or by switchingcells to low serum media and incubating overnight. Cells are treated for1, 6, or 24 hours with either vector control supernatant or samplesupernatant (or purified/partially purified protein preparations inbuffer). Total RNA is isolated; for example, by using Trizol extractionor by using the Ambion RNAqueous™-4PCR RNA isolation system. Expressionlevels of multiple genes are analyzed using Taqman®, and expression inthe test sample is compared to control vector samples to identify genesinduced or repressed. Each of the above described techniques are wellknown to, and routinely performed by, those of ordinary skill in theart.

Table 1F indicates particular disease classes and preferred indicationsfor which polynucleotides, polypeptides, or antibodies of the presentinvention may be used in detecting, diagnosing, preventing, treatingand/or ameliorating said diseases and disorders based on “target” geneexpression patterns which may be up- or down-regulated bypolynucleotides (and the encoded polypeptides) corresponding to eachindicated cDNA Clone ID (shown in Table 1F, Column 2).

Thus, in preferred embodiments, the present invention encompasses amethod of detecting, diagnosing, preventing, treating, and/orameliorating a disease or disorder listed in the “Disease Class” and/or“Preferred Indication” columns of Table 1F; comprising administering toa patient in which such detection, diagnosis, prevention, or treatmentis desired a protein, nucleic acid, or antibody of the invention (orfragment or variant thereof) in an amount effective to detect, diagnose,prevent, treat, or ameliorate the disease or disorder. The first andsecond columns of Table 1D show the “Gene No.” and “cDNA Clone ID No.”,respectively, indicating certain nucleic acids and proteins (orantibodies against the same) of the invention (including polynucleotide,polypeptide, and antibody fragments or variants thereof) that may beused in detecting, diagnosing, preventing, treating, or ameliorating thedisease(s) or disorder(s) indicated in the corresponding row in the“Disease Class” or “Preferred Indication” Columns of Table 1F.

In another embodiment, the present invention also encompasses methods ofdetecting, diagnosing, preventing, treating, or ameliorating a diseaseor disorder listed in the “Disease Class” or “Preferred Indication”Columns of Table 1F; comprising administering to a patient combinationsof the proteins, nucleic acids, or antibodies of the invention (orfragments or variants thereof), sharing similar indications as shown inthe corresponding rows in the “Disease Class” or “Preferred Indication”Columns of Table 1F.

The “Disease Class” Column of Table 1F provides a categorizeddescriptive heading for diseases, disorders, and/or conditions (morefully described below) that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Preferred Indication” Column of Table 1F describes diseases,disorders, and/or conditions that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Cell Line” and “Exemplary Targets” Columns of Table 1F indicateparticular cell lines and target genes, respectively, which may showaltered gene expression patterns (i.e., up- or down-regulation of theindicated target gene) in Taqman® assays, performed as described above,utilizing polynucleotides of the cDNA Clone ID shown in thecorresponding row. Alteration of expression patterns of the indicated“Exemplary Target” genes is correlated with a particular “Disease Class”and/or “Preferred Indication” as shown in the corresponding row underthe respective column headings.

The “Exemplary Accessions” Column indicates GenBank Accessions(available online through the National Center for BiotechnologyInformation (NCBI) at http://www.ncbi.nlm.nih.gov/) which correspond tothe “Exemplary Targets” shown in the adjacent row.

The recitation of “Cancer” in the “Disease Class” Column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof) may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorateneoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., asdescribed below under “Hyperproliferative Disorders”).

The recitation of “Immune” in the “Disease Class” column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), blood disorders (e.g., asdescribed below under “Immune Activity” “Cardiovascular Disorders”and/or “Blood-Related Disorders”), and infections (e.g., as describedbelow under “Infectious Disease”).

The recitation of “Angiogenesis” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), diseases and/or disordersof the cardiovascular system (e.g., as described below under“Cardiovascular Disorders”), diseases and/or disorders involvingcellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), diseases and/or disorders involvingangiogenesis (e.g., as described below under “Anti-AngiogenesisActivity”), to promote or inhibit cell or tissue regeneration (e.g., asdescribed below under “Regeneration”), or to promote wound healing(e.g., as described below under “Wound Healing and Epithelial CellProliferation”).

The recitation of “Diabetes” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diabetes(including diabetes mellitus types I and II), as well as diseases and/ordisorders associated with, or consequential to, diabetes (e.g. asdescribed below under “Endocrine Disorders,” “Renal Disorders,” and“Gastrointestinal Disorders”).

Description of Table 2

Table 2 summarizes homology and features of some of the polypeptides ofthe invention. The first column provides a unique clone identifier,“Clone ID:”, corresponding to a cDNA clone disclosed in Table 1A or 1B.The second column provides the unique contig identifier, “Contig ID:”corresponding to contigs in Table 1B and allowing for correlation withthe information in Table 1B. The third column provides the sequenceidentifier, “SEQ ID NO:X”, for the contig polynucleotide sequence. Thefourth column provides the analysis method by which thehomology/identity disclosed in the Table was determined. Comparisonswere made between polypeptides encoded by the polynucleotides of theinvention and either a non-redundant protein database (herein referredto as “NR”), or a database of protein families (herein referred to as“PFAM”) as further described below. The fifth column provides adescription of the PFAM/NR hit having a significant match to apolypeptide of the invention. Column six provides the accession numberof the PFAM/NR hit disclosed in the fifth column. Column seven,“Score/Percent Identity”, provides a quality score or the percentidentity, of the hit disclosed in columns five and six. Columns 8 and 9,“NT From” and “NT To” respectively, delineate the polynucleotides in“SEQ ID NO:X” that encode a polypeptide having a significant match tothe PFAM/NR database as disclosed in the fifth and sixth columns. Inspecific embodiments polypeptides of the invention comprise, oralternatively consist of, an amino acid sequence encoded by apolynucleotide in SEQ ID NO:X as delineated in columns 8 and 9, orfragments or variants thereof.

Description of Table 3

Table 3 provides polynucleotide sequences that may be disclaimedaccording to certain embodiments of the invention. The first columnprovides a unique clone identifier, “Clone ID”, for a cDNA clone relatedto contig sequences disclosed in Table 1B. The second column providesthe sequence identifier, “SEQ ID NO:X”, for contig sequences disclosedin Table 1A and/or 1B. The third column provides the unique contigidentifier, “Contig ID:”, for contigs disclosed in Table 1B. The fourthcolumn provides a unique integer ‘a’ where ‘a’ is any integer between 1and the final nucleotide minus 15 of SEQ ID NO:X, and the fifth columnprovides a unique integer ‘b’ where ‘b’ is any integer between 15 andthe final nucleotide of SEQ ID NO:X, where both a and b correspond tothe positions of nucleotide residues shown in SEQ ID NO:X, and where bis greater than or equal to a +14. For each of the polynucleotides shownas SEQ ID NO:X, the uniquely defined integers can be substituted intothe general formula of a-b, and used to describe polynucleotides whichmay be preferably excluded from the invention. In certain embodiments,preferably excluded from the invention are at least one, two, three,four, five, ten, or more of the polynucleotide sequence(s) having theaccession number(s) disclosed in the sixth column of this Table(including for example, published sequence in connection with aparticular BAC clone). In further embodiments, preferably excluded fromthe invention are the specific polynucleotide sequence(s) contained inthe clones corresponding to at least one, two, three, four, five, ten,or more of the available material having the accession numbersidentified in the sixth column of this Table (including for example, theactual sequence contained in an identified BAC clone).

Description of Table 4

Table 4 provides a key to the tissue/cell source identifier codedisclosed in Table 1B.2, column 5. Column 1 provides the tissue/cellsource identifier code disclosed in Table 1B.2, Column 5. Columns 2-5provide a description of the tissue or cell source. Note that“Description” and “Tissue” sources (i.e. columns 2 and 3) having theprefix “a_” indicates organs, tissues, or cells derived from “adult”sources. Codes corresponding to diseased tissues are indicated in column6 with the word “disease.” The use of the word “disease” in column 6 isnon-limiting. The tissue or cell source may be specific (e.g. aneoplasm), or may be disease-associated (e.g., a tissue sample from anormal portion of a diseased organ). Furthermore, tissues and/or cellslacking the “disease” designation may still be derived from sourcesdirectly or indirectly involved in a disease state or disorder, andtherefore may have a further utility in that disease state or disorder.In numerous cases where the tissue/cell source is a library, column 7identifies the vector used to generate the library.

Description of Table 5

Table 5 provides a key to the OMIM reference identification numbersdisclosed in Table 1B.1, column 9. OMIM reference identification numbers(Table 5, Column 1) were derived from Online Mendelian Inheritance inMan (Online Mendelian Inheritance in Man, OMIM. McKusick-NathansInstitute for Genetic Medicine, Johns Hopkins University (Baltimore,Md.) and National Center for Biotechnology Information, National Libraryof Medicine, (Bethesda, Md.) 2000. World Wide Web URL:http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseasesassociated with the cytologic band disclosed in Table 1B.1, column 8, asdetermined using the Morbid Map database.

Description of Table 6

Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCCdesignation numbers of deposits made with the ATCC in connection withthe present application. These deposits were made in addition to thosedescribed in the Table 1A.

Description of Table 7

Table 7 shows the cDNA libraries sequenced, and ATCC designation numbersand vector information relating to these cDNA libraries.

The first column shows the first four letters indicating the Libraryfrom which each library clone was derived. The second column indicatesthe catalogued tissue description for the corresponding libraries. Thethird column indicates the vector containing the corresponding clones.The fourth column shows the ATCC deposit designation for each libraryclone as indicated by the deposit information in Table 6.

Definitions

The following definitions are provided to facilitate understanding ofcertain terms used throughout this specification.

In the present invention, “isolated” refers to material removed from itsoriginal environment (e.g., the natural environment if it is naturallyoccurring), and thus is altered “by the hand of man” from its naturalstate. For example, an isolated polynucleotide could be part of a vectoror a composition of matter, or could be contained within a cell, andstill be “isolated” because that vector, composition of matter, orparticular cell is not the original environment of the polynucleotide.The term “isolated” does not refer to genomic or cDNA libraries, wholecell total or mRNA preparations, genomic DNA preparations (includingthose separated by electrophoresis and transferred onto blots), shearedwhole cell genomic DNA preparations or other compositions where the artdemonstrates no distinguishing features of the polynucleotide/sequencesof the present invention.

In the present invention, a “secreted” protein refers to those proteinscapable of being directed to the ER, secretory vesicles, or theextracellular space as a result of a signal sequence, as well as thoseproteins released into the extracellular space without necessarilycontaining a signal sequence. If the secreted protein is released intothe extracellular space, the secreted protein can undergo extracellularprocessing to produce a “mature” protein. Release into the extracellularspace can occur by many mechanisms, including exocytosis and proteolyticcleavage.

As used herein, a “polynucleotide” refers to a molecule having a nucleicacid sequence encoding SEQ ID NO:Y or a fragment or variant thereof(e.g., the polypeptide delinated in columns fourteen and fifteen ofTable 1A); a nucleic acid sequence contained in SEQ ID NO:X (asdescribed in column 5 of Table 1A and/or column 3 of Table 1B) or thecomplement thereof; a cDNA sequence contained in Clone ID: (as describedin column 2 of Table 1A and/or 1B and contained within a librarydeposited with the ATCC); a nucleotide sequence encoding the polypeptideencoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6(EXON From-To) of Table 1C or a fragment or variant thereof; or anucleotide coding sequence in SEQ ID NO:B as defined in column 6 ofTable 1C or the complement thereof. For example, the polynucleotide cancontain the nucleotide sequence of the full length cDNA sequence,including the 5′ and 3′ untranslated sequences, the coding region, aswell as fragments, epitopes, domains, and variants of the nucleic acidsequence. Moreover, as used herein, a “polypeptide” refers to a moleculehaving an amino acid sequence encoded by a polynucleotide of theinvention as broadly defined (obviously excluding poly-Phenylalanine orpoly-Lysine peptide sequences which result from translation of a polyAtail of a sequence corresponding to a cDNA).

In the present invention, “SEQ ID NO:X” was often generated byoverlapping sequences contained in multiple clones (contig analysis). Arepresentative clone containing all or most of the sequence for SEQ IDNO:X is deposited at Human Genome Sciences, Inc. (HGS) in a cataloguedand archived library. As shown, for example, in column 2 of Table 1B,each clone is identified by a cDNA Clone ID (identifier generallyreferred to herein as Clone ID:). Each Clone ID is unique to anindividual clone and the Clone ID is all the information needed toretrieve a given clone from the HGS library. Table 7 provides a list ofthe deposited cDNA libraries. One can use the Clone ID: to determine thelibrary source by reference to Tables 6 and 7. Table 7 lists thedeposited cDNA libraries by name and links each library to an ATCCDeposit. Library names contain four characters, for example, “HTWE.” Thename of a cDNA clone (Clone ID) isolated from that library begins withthe same four characters, for example “HTWEP07”. As mentioned below,Table 1A and/or 1B correlates the Clone ID names with SEQ ID NO:X. Thus,starting with an SEQ ID NO:X, one can use Tables 1A, 1B, 6, 7, and 9 todetermine the corresponding Clone ID, which library it came from andwhich ATCC deposit the library is contained in. Furthermore, it ispossible to retrieve a given cDNA clone from the source library bytechniques known in the art and described elsewhere herein. The ATCC islocated at 10801 University Boulevard, Manassas, Va. 20110-2209, USA.The ATCC deposits were made pursuant to the terms of the Budapest Treatyon the international recognition of the deposit of microorganisms forthe purposes of patent procedure.

In specific embodiments, the polynucleotides of the invention are atleast 15, at least 30, at least 50, at least 100, at least 125, at least500, or at least 1000 continuous nucleotides but are less than or equalto 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb,2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides ofthe invention comprise a portion of the coding sequences, as disclosedherein, but do not comprise all or a portion of any intron. In anotherembodiment, the polynucleotides comprising coding sequences do notcontain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ tothe gene of interest in the genome). In other embodiments, thepolynucleotides of the invention do not contain the coding sequence ofmore than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1genomic flanking gene(s).

A “polynucleotide” of the present invention also includes thosepolynucleotides capable of hybridizing, under stringent hybridizationconditions, to sequences contained in SEQ ID NO:X, or the complementthereof (e.g., the complement of any one, two, three, four, or more ofthe polynucleotide fragments described herein), the polynucleotidesequence delineated in columns 7 and 8 of Table 1A or the complementthereof, the polynucleotide sequence delineated in columns 8 and 9 ofTable 2 or the complement thereof, and/or cDNA sequences contained inClone ID: (e.g., the complement of any one, two, three, four, or more ofthe polynucleotide fragments, or the cDNA clone within the pool of cDNAclones deposited with the ATCC, described herein), and/or thepolynucleotide sequence delineated in column 6 of Table 1C or thecomplement thereof. “Stringent hybridization conditions” refers to anovernight incubation at 42 degree C. in a solution comprising 50%formamide, 5×SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodiumphosphate (pH 7.6), 5× Denhardt's solution, 10% dextran sulfate, and 20μg/ml denatured, sheared salmon sperm DNA, followed by washing thefilters in 0.1×SSC at about 65 degree C.

Also contemplated are nucleic acid molecules that hybridize to thepolynucleotides of the present invention at lower stringencyhybridization conditions. Changes in the stringency of hybridization andsignal detection are primarily accomplished through the manipulation offormamide concentration (lower percentages of formamide result inlowered stringency); salt conditions, or temperature. For example, lowerstringency conditions include an overnight incubation at 37 degree C. ina solution comprising 6×SSPE (20×SSPE=3M NaCl; 0.2M NaH₂PO₄; 0.02M EDTA,pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA;followed by washes at 50 degree C. with 1×SSPE, 0.1% SDS. In addition,to achieve even lower stringency, washes performed following stringenthybridization can be done at higher salt concentrations (e.g. 5×SSC).

Note that variations in the above conditions may be accomplished throughthe inclusion and/or substitution of alternate blocking reagents used tosuppress background in hybridization experiments. Typical blockingreagents include Denhardt's reagent, BLOTTO, heparin, denatured salmonsperm DNA, and commercially available proprietary formulations. Theinclusion of specific blocking reagents may require modification of thehybridization conditions described above, due to problems withcompatibility.

Of course, a polynucleotide which hybridizes only to polyA+ sequences(such as any 3′ terminal polyA+ tract of a cDNA shown in the sequencelisting), or to a complementary stretch of T (or U) residues, would notbe included in the definition of “polynucleotide,” since such apolynucleotide would hybridize to any nucleic acid molecule containing apoly (A) stretch or the complement thereof (e.g., practically anydouble-stranded cDNA clone generated using oligo dT as a primer).

The polynucleotide of the present invention can be composed of anypolyribonucleotide or polydeoxribonucleotide, which may be unmodifiedRNA or DNA or modified RNA or DNA. For example, polynucleotides can becomposed of single- and double-stranded DNA, DNA that is a mixture ofsingle- and double-stranded regions, single- and double-stranded RNA,and RNA that is mixture of single- and double-stranded regions, hybridmolecules comprising DNA and RNA that may be single-stranded or, moretypically, double-stranded or a mixture of single- and double-strandedregions. In addition, the polynucleotide can be composed oftriple-stranded regions comprising RNA or DNA or both RNA and DNA. Apolynucleotide may also contain one or more modified bases or DNA or RNAbackbones modified for stability or for other reasons. “Modified” basesinclude, for example, tritylated bases and unusual bases such asinosine. A variety of modifications can be made to DNA and RNA; thus,“polynucleotide” embraces chemically, enzymatically, or metabolicallymodified forms.

In specific embodiments, the polynucleotides of the invention are atleast 15, at least 30, at least 50, at least 100, at least 125, at least500, or at least 1000 continuous nucleotides but are less than or equalto 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb,2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides ofthe invention comprise a portion of the coding sequences, as disclosedherein, but do not comprise all or a portion of any intron. In anotherembodiment, the polynucleotides comprising coding sequences do notcontain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ tothe gene of interest in the genome). In other embodiments, thepolynucleotides of the invention do not contain the coding sequence ofmore than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1genomic flanking gene(s).

“SEQ ID NO:X” refers to a polynucleotide sequence described in column 5of Table 1A, while “SEQ ID NO:Y” refers to a polypeptide sequencedescribed in column 10 of Table 1A. SEQ ID NO:X is identified by aninteger specified in column 6 of Table 1A. The polypeptide sequence SEQID NO:Y is a translated open reading frame (ORF) encoded bypolynucleotide SEQ ID NO:X. The polynucleotide sequences are shown inthe sequence listing immediately followed by all of the polypeptidesequences. Thus, a polypeptide sequence corresponding to polynucleotidesequence SEQ ID NO:2 is the first polypeptide sequence shown in thesequence listing. The second polypeptide sequence corresponds to thepolynucleotide sequence shown as SEQ ID NO:3, and so on.

The polypeptide of the present invention can be composed of amino acidsjoined to each other by peptide bonds or modified peptide bonds, i.e.,peptide isosteres, and may contain amino acids other than the 20gene-encoded amino acids. The polypeptides may be modified by eithernatural processes, such as posttranslational processing, or by chemicalmodification techniques which are well known in the art. Suchmodifications are well described in basic texts and in more detailedmonographs, as well as in a voluminous research literature.Modifications can occur anywhere in a polypeptide, including the peptidebackbone, the amino acid side-chains and the amino or carboxyl termini.It will be appreciated that the same type of modification may be presentin the same or varying degrees at several sites in a given polypeptide.Also, a given polypeptide may contain many types of modifications.Polypeptides may be branched, for example, as a result ofubiquitination, and they may be cyclic, with or without branching.Cyclic, branched, and branched cyclic polypeptides may result fromposttranslation natural processes or may be made by synthetic methods.Modifications include acetylation, acylation, ADP-ribosylation,amidation, covalent attachment of flavin, covalent attachment of a hememoiety, covalent attachment of a nucleotide or nucleotide derivative,covalent attachment of a lipid or lipid derivative, covalent attachmentof phosphotidylinositol, cross-linking, cyclization, disulfide bondformation, demethylation, formation of covalent cross-links, formationof cysteine, formation of pyroglutamate, formylation,gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation,iodination, methylation, myristoylation, oxidation, pegylation,proteolytic processing, phosphorylation, prenylation, racemization,selenoylation, sulfation, transfer-RNA mediated addition of amino acidsto proteins such as arginylation, and ubiquitination. (See, forinstance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.Creighton, W.H. Freeman and Company, New York (1993); POSTTRANSLATIONALCOVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press,New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646(1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

“SEQ ID NO:X” refers to a polynucleotide sequence described, forexample, in Tables 1A, 1B or 2, while “SEQ ID NO:Y” refers to apolypeptide sequence described in column 11 of Table 1A and or column 6of Table 1B.1. SEQ ID NO:X is identified by an integer specified incolumn 4 of Table 1B.1. The polypeptide sequence SEQ ID NO:Y is atranslated open reading frame (ORF) encoded by polynucleotide SEQ IDNO:X. “Clone ID:” refers to a cDNA clone described in column 2 of Table1A and/or 1B.

“A polypeptide having functional activity” refers to a polypeptidecapable of displaying one or more known functional activities associatedwith a full-length (complete) protein. Such functional activitiesinclude, but are not limited to, biological activity, antigenicity[ability to bind (or compete with a polypeptide for binding) to ananti-polypeptide antibody], immunogenicity (ability to generate antibodywhich binds to a specific polypeptide of the invention), ability to formmultimers with polypeptides of the invention, and ability to bind to areceptor or ligand for a polypeptide.

The polypeptides of the invention can be assayed for functional activity(e.g. biological activity) using or routinely modifying assays known inthe art, as well as assays described herein. Specifically, one of skillin the art may routinely assay secreted polypeptides (includingfragments and variants) of the invention for activity using assays asdescribed in the examples section below.

“A polypeptide having biological activity” refers to a polypeptideexhibiting activity similar to, but not necessarily identical to, anactivity of a polypeptide of the present invention, including matureforms, as measured in a particular biological assay, with or withoutdose dependency. In the case where dose dependency does exist, it neednot be identical to that of the polypeptide, but rather substantiallysimilar to the dose-dependence in a given activity as compared to thepolypeptide of the present invention (i.e., the candidate polypeptidewill exhibit greater activity or not more than about 25-fold less and,preferably, not more than about tenfold less activity, and mostpreferably, not more than about three-fold less activity relative to thepolypeptide of the present invention).

Tables

Table 1A

Table 1A summarizes information concerning certain polynucleotides andpolypeptides of the invention. The first column provides the gene numberin the application for each clone identifier. The second column providesa unique clone identifier, “Clone ID:”, for a cDNA clone related to eachcontig sequence disclosed in Table 1A. Third column, the cDNA Clonesidentified in the second column were deposited as indicated in the thirdcolumn (i.e. by ATCC Deposit No: Z and deposit date). Some of thedeposits contain multiple different clones corresponding to the samegene. In the fourth column, “Vector” refers to the type of vectorcontained in the corresponding cDNA Clone identified in the secondcolumn. In the fifth column, the nucleotide sequence identified as “NTSEQ ID NO:X” was assembled from partially homologous (“overlapping”)sequences obtained from the corresponding cDNA clone identified in thesecond column and, in some cases, from additional related cDNA clones.The overlapping sequences were assembled into a single contiguoussequence of high redundancy (usually three to five overlapping sequencesat each nucleotide position), resulting in a final sequence identifiedas SEQ ID NO:X. In the sixth column, “Total NT Seq.” refers to the totalnumber of nucleotides in the contig sequence identified as SEQ ID NO:X.”The deposited clone may contain all or most of these sequences,reflected by the nucleotide position indicated as “5′ NT of Clone Seq.”(seventh column) and the “3′ NT of Clone Seq.” (eighth column) of SEQ IDNO:X. In the ninth column, the nucleotide position of SEQ ID NO:X of theputative start codon (methionine) is identified as “5′ NT of StartCodon.” Similarly, in column ten, the nucleotide position of SEQ ID NO:Xof the predicted signal sequence is identified as “5′ NT of First AA ofSignal Pep.” In the eleventh column, the translated amino acid sequence,beginning with the methionine, is identified as “AA SEQ ID NO:Y,”although other reading frames can also be routinely translated usingknown molecular biology techniques. The polypeptides produced by thesealternative open reading frames are specifically contemplated by thepresent invention.

In the twelfth and thirteenth columns of Table 1A, the first and lastamino acid position of SEQ ID NO:Y of the predicted signal peptide isidentified as “First AA of Sig Pep” and “Last AA of Sig Pep.” In thefourteenth column, the predicted first amino acid position of SEQ IDNO:Y of the secreted portion is identified as “Predicted First AA ofSecreted Portion”. The amino acid position of SEQ ID NO:Y of the lastamino acid encoded by the open reading frame is identified in thefifteenth column as “Last AA of ORF”.

SEQ ID NO:X (where X may be any of the polynucleotide sequencesdisclosed in the sequence listing) and the translated SEQ ID NO:Y (whereY may be any of the polypeptide sequences disclosed in the sequencelisting) are sufficiently accurate and otherwise suitable for a varietyof uses well known in the art and described further below. For instance,SEQ ID NO:X is useful for designing nucleic acid hybridization probesthat will detect nucleic acid sequences contained in SEQ ID NO:X or thecDNA contained in the deposited clone. These probes will also hybridizeto nucleic acid molecules in biological samples, thereby enabling avariety of forensic and diagnostic methods of the invention. Similarly,polypeptides identified from SEQ ID NO:Y may be used, for example, togenerate antibodies which bind specifically to proteins containing thepolypeptides and the secreted proteins encoded by the cDNA clonesidentified in Table 1A and/or elsewhere herein

Nevertheless, DNA sequences generated by sequencing reactions cancontain sequencing errors. The errors exist as misidentifiednucleotides, or as insertions or deletions of nucleotides in thegenerated DNA sequence. The erroneously inserted or deleted nucleotidescause frame shifts in the reading frames of the predicted amino acidsequence. In these cases, the predicted amino acid sequence divergesfrom the actual amino acid sequence, even though the generated DNAsequence may be greater than 99.9% identical to the actual DNA sequence(for example, one base insertion or deletion in an open reading frame ofover 1000 bases).

Accordingly, for those applications requiring precision in thenucleotide sequence or the amino acid sequence, the present inventionprovides not only the generated nucleotide sequence identified as SEQ IDNO:X, and the predicted translated amino acid sequence identified as SEQID NO:Y, but also a sample of plasmid DNA containing a human cDNA of theinvention deposited with the ATCC, as set forth in Table 1A. Thenucleotide sequence of each deposited plasmid can readily be determinedby sequencing the deposited plasmid in accordance with known methods

The predicted amino acid sequence can then be verified from suchdeposits. Moreover, the amino acid sequence of the protein encoded by aparticular plasmid can also be directly determined by peptide sequencingor by expressing the protein in a suitable host cell containing thedeposited human cDNA, collecting the protein, and determining itssequence.

Also provided in Table 1A is the name of the vector which contains thecDNA plasmid. Each vector is routinely used in the art. The followingadditional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Phagemid pBS may be excised fromthe Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excisedfrom the Zap Express vector. Both phagemids may be transformed into E.coli strain XL-1 Blue, also available from Stratagene

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, wereobtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md.20897. All Sport vectors contain an ampicillin resistance gene and maybe transformed into E. coli strain DH10B, also available from LifeTechnologies. See, for instance, Gruber, C. E., et al., Focus 15:59(1993). Vector lafmid BA (Bento Soares, Columbia University, New York,N.Y.) contains an ampicillin resistance gene and can be transformed intoE. coli strain XL-1 Blue. Vector pCR®2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ IDNO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID). Thecorresponding gene can be isolated in accordance with known methodsusing the sequence information disclosed herein. Such methods include,but are not limited to, preparing probes or primers from the disclosedsequence and identifying or amplifying the corresponding gene fromappropriate sources of genomic material.

Also provided in the present invention are allelic variants, orthologs,and/or species homologs. Procedures known in the art can be used toobtain full-length genes, allelic variants, splice variants, full-lengthcoding portions, orthologs, and/or species homologs of genescorresponding to SEQ ID NO:X and SEQ ID NO:Y using information from thesequences disclosed herein or the clones deposited with the ATCC. Forexample, allelic variants and/or species homologs may be isolated andidentified by making suitable probes or primers from the sequencesprovided herein and screening a suitable nucleic acid source for allelicvariants and/or the desired homologue.

The present invention provides a polynucleotide comprising, oralternatively consisting of, the nucleic acid sequence of SEQ ID NO:Xand/or a cDNA contained in ATCC Deposit No. Z. The present inventionalso provides a polypeptide comprising, or alternatively, consisting of,the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ IDNO:X, and/or a polypeptide encoded by a cDNA contained in ATCC depositNo. Z. Polynucleotides encoding a polypeptide comprising, oralternatively consisting of the polypeptide sequence of SEQ ID NO:Y, apolypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by thecDNA contained in ATCC Deposit No. Z, are also encompassed by theinvention. The present invention further encompasses a polynucleotidecomprising, or alternatively consisting of the complement of the nucleicacid sequence of SEQ ID NO:X, and/or the complement of the coding strandof the cDNA contained in ATCC Deposit No. Z. LENGTHY TABLE REFERENCEDHERE US20070048297A1-20070301-T00001 Please refer to the end of thespecification for access instructions.Table 1B (Comprised of Tables 1B.1 and 1B.2)

The first column in Table 1B.1 and Table 1B.2 provides the gene numberin the application corresponding to the clone identifier. The secondcolumn in Table 1B.1 and Table 1B.2 provides a unique “Clone ID:” forthe cDNA clone related to each contig sequence disclosed in Table 1B.1and Table 1B.2. This clone ID references the cDNA clone which containsat least the 5′ most sequence of the assembled contig and at least aportion of SEQ ID NO:X as determined by directly sequencing thereferenced clone. The referenced clone may have more sequence thandescribed in the sequence listing or the clone may have less. In thevast majority of cases, however, the clone is believed to encode afull-length polypeptide. In the case where a clone is not full-length, afull-length cDNA can be obtained by methods described elsewhere herein.The third column in Table 1B.1 and Table 1B.2 provides a unique “ContigID” identification for each contig sequence. The fourth column in Table1B.1 and Table 1B.2 provides the “SEQ ID NO:” identifier for each of thecontig polynucleotide sequences disclosed in Table 1B.

Table 1B.1

The fifth column in Table 1B.1, “ORF (From-To)”, provides the location(i.e., nucleotide position numbers) within the polynucleotide sequence“SEQ ID NO:X” that delineate the preferred open reading frame (ORF)shown in the sequence listing and referenced in Table 1B.1, column 6, asSEQ ID NO:Y. Where the nucleotide position number “To” is lower than thenucleotide position number “From”, the preferred ORF is the reversecomplement of the referenced polynucleotide sequence. The sixth columnin Table 1B.1 provides the corresponding SEQ ID NO:Y for the polypeptidesequence encoded by the preferred ORF delineated in column 5. In oneembodiment, the invention provides an amino acid sequence comprising, oralternatively consisting of, a polypeptide encoded by the portion of SEQID NO:X delineated by “ORF (From-To)”. Also provided are polynucleotidesencoding such amino acid sequences and the complementary strand thereto.Column 7 in Table 1B.1 lists residues comprising epitopes contained inthe polypeptides encoded by the preferred ORF (SEQ ID NO:Y), aspredicted using the algorithm of Jameson and Wolf, (1988) Comp. Appl.Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performedusing the computer program PROTEAN (Version 3.11 for the PowerMacIntosh, DNASTAR, Inc., 1228 South Park Street Madison, Wis.). Inspecific embodiments, polypeptides of the invention comprise, oralternatively consist of, at least one, two, three, four, five or moreof the predicted epitopes as described in Table 1B. It will beappreciated that depending on the analytical criteria used to predictantigenic determinants, the exact address of the determinant may varyslightly.

Column 8 in Table 1B.1 provides a chromosomal map location for certainpolynucleotides of the invention. Chromosomal location was determined byfinding exact matches to EST and cDNA sequences contained in the NCBI(National Center for Biotechnology Information) UniGene database. Eachsequence in the UniGene database is assigned to a “cluster”; all of theESTs, cDNAs, and STSs in a cluster are believed to be derived from asingle gene. Chromosomal mapping data is often available for one or moresequence(s) in a UniGene cluster; this data (if consistent) is thenapplied to the cluster as a whole. Thus, it is possible to infer thechromosomal location of a new polynucleotide sequence by determining itsidentity with a mapped UniGene cluster.

A modified version of the computer program BLASTN (Altshul, et al., J.Mol. Biol. 215:403-410 (1990), and Gish, and States, Nat. Genet.3:266-272) (1993) was used to search the UniGene database for EST orcDNA sequences that contain exact or near-exact matches to apolynucleotide sequence of the invention (the ‘Query’). A sequence fromthe UniGene database (the ‘Subject’) was said to be an exact match if itcontained a segment of 50 nucleotides in length such that 48 of thosenucleotides were in the same order as found in the Query sequence. Ifall of the matches that met this criteria were in the same UniGenecluster, and mapping data was available for this cluster, it isindicated in Table 1B under the heading “Cytologic Band”. Where acluster had been further localized to a distinct cytologic band, thatband is disclosed; where no banding information was available, but thegene had been localized to a single chromosome, the chromosome isdisclosed.

Once a presumptive chromosomal location was determined for apolynucleotide of the invention, an associated disease locus wasidentified by comparison with a database of diseases which have beenexperimentally associated with genetic loci. The database used was theMorbid Map, derived from OMIM™ and National Center for BiotechnologyInformation, National Library of Medicine (Bethesda, Md.) 2000. If theputative chromosomal location of a polynucleotide of the invention(Query sequence) was associated with a disease in the Morbid Mapdatabase, an OMIM reference identification number was noted in column 9,Table 1B.1, labelled “OMIM Disease Reference(s). Table 5 is a key to theOMIM reference identification numbers (column 1), and provides adescription of the associated disease in Column 2.

Table 1B.2

Column 5, in Table 1B.2, provides an expression profile and libraryCode:Count for each of the contig sequences (SEQ ID NO:X) disclosed inTable 1B, which can routinely be combined with the information providedin Table 4 and used to determine the tissues, cells, and/or cell linelibraries which predominantly express the polynucleotides of theinvention. The first number in Table 1B.2, column 5 (preceding thecolon), represents the tissue/cell source identifier code correspondingto the code and description provided in Table 4. The second number incolumn 5 (following the colon) represents the number of times a sequencecorresponding to the reference polynucleotide sequence was identified inthe corresponding tissue/cell source. Those tissue/cell sourceidentifier codes in which the first two letters are “AR” designateinformation generated using DNA array technology. Utilizing thistechnology, cDNAs were amplified by PCR and then transferred, induplicate, onto the array. Gene expression was assayed throughhybridization of first strand cDNA probes to the DNA array. cDNA probeswere generated from total RNA extracted from a variety of differenttissues and cell lines. Probe synthesis was performed in the presence of³³P dCTP, using oligo (dT) to prime reverse transcription. Afterhybridization, high stringency washing conditions were employed toremove non-specific hybrids from the array. The remaining signal,emanating from each gene target, was measured using a Phosphorimager.Gene expression was reported as Phosphor Stimulating Luminescence (PSL)which reflects the level of phosphor signal generated from the probehybridized to each of the gene targets represented on the array. A localbackground signal subtraction was performed before the total signalgenerated from each array was used to normalize gene expression betweenthe different hybridizations. The value presented after “[array code]:”represents the mean of the duplicate values, following backgroundsubtraction and probe normalization. One of skill in the art couldroutinely use this information to identify normal and/or diseasedtissue(s) which show a predominant expression pattern of thecorresponding polynucleotide of the invention or to identifypolynucleotides which show predominant and/or specific tissue and/orcell expression. LENGTHY TABLE REFERENCED HEREUS20070048297A1-20070301-T00002 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070048297A1-20070301-T00003 Please refer to the end of thespecification for access instructions.

Table 1C summarizes additional polynucleotides encompassed by theinvention (including cDNA clones related to the sequences (Clone ID:),contig sequences (contig identifier (Contig ID:) contig nucleotidesequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ IDNO:B). The first column provides a unique clone identifier, “Clone ID:”,for a cDNA clone related to each contig sequence. The second columnprovides the sequence identifier, “SEQ ID NO:X”, for each contigsequence. The third column provides a unique contig identifier, “ContigID:” for each contig sequence. The fourth column, provides a BACidentifier “BAC ID NO:A” for the BAC clone referenced in thecorresponding row of the table. The fifth column provides the nucleotidesequence identifier, “SEQ ID NO:B” for a fragment of the BAC cloneidentified in column four of the corresponding row of the table. Thesixth column, “Exon From-To”, provides the location (i.e., nucleotideposition numbers) within the polynucleotide sequence of SEQ ID NO:Bwhich delineate certain polynucleotides of the invention that are alsoexemplary members of polynucleotide sequences that encode polypeptidesof the invention (e.g., polypeptides containing amino acid sequencesencoded by the polynucleotide sequences delineated in column six, andfragments and variants thereof). LENGTHY TABLE REFERENCED HEREUS20070048297A1-20070301-T00004 Please refer to the end of thespecification for access instructions.

Tables 1D and 1E: The polynucleotides or polypeptides, or agonists orantagonists of the present invention can be used in assays to test forone or more biological activities. If these polynucleotides andpolypeptides do exhibit activity in a particular assay, it is likelythat these molecules may be involved in the diseases associated with thebiological activity. Thus, the polynucleotides or polypeptides, oragonists or antagonists could be used to treat the associated disease.

The present invention encompasses methods of detecting, preventing,diagnosing, prognosticating, treating, and/or ameliorating a disease ordisorder. In preferred embodiments, the present invention encompasses amethod of treating a disease or disorder listed in the “PreferredIndications” columns of Table 1D and Table 1E; comprising administeringto a patient (in which such treatment, prevention, or amelioration isdesired) a protein, nucleic acid, or antibody of the invention (orfragment or variant thereof) in an amount effective to treat, prevent,diagnose, or ameliorate the disease or disorder. The first and seccondcolumns of Table 1D show the “Gene No.” and “cDNA Clone ID No.”,respectively, indicating certain nucleic acids and proteins (orantibodies against the same) of the invention (including polynucleotide,polypeptide, and antibody fragments or variants thereof) that may beused in preventing, treating, diagnosing, or ameliorating the disease(s)or disorder(s) indicated in the corresponding row in Column 3 of Table1D.

In another embodiment, the present invention also encompasses methods ofpreventing, treating, diagnosing, or ameliorating a disease or disorderlisted in the “Preferred Indications” column of Table 1D and Table 1E;comprising administering to a patient combinations of the proteins,nucleic acids, or antibodies of the invention (or fragments or variantsthereof), sharing similar indications as shown in the corresponding rowsin Colum 3 of Table 1D.

The “Preferred Indications” columns of Table 1D and Table 1E describediseases, disorders, and/or conditions that may be treated, prevented,diagnosed, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The recitation of “Cancer” in the “Preferred Indications” columnsindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof) maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g.,leukemias, cancers, and/or as described below under “HyperproliferativeDisorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cancer” recitationin the “Preferred Indication” column of Table 1D may be used forexample, to diagnose, treat, prevent, and/or ameliorate a neoplasmlocated in a tissue selected from the group consisting of: colon,abdomen, bone, breast, digestive system, liver, pancreas, prostate,peritoneum, lung, blood (e.g., leukemia), endocrine glands (adrenal,parathyroid, pituitary, testicles, ovary, thymus, thyroid), uterus, eye,head and neck, nervous (central and peripheral), lymphatic system,pelvic, skin, soft tissue, spleen, thoracic, and urogenital.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cancer” recitationin the “Preferred Indication” column of Table 1D, may be used forexample, to diagnose, treat, prevent, and/or ameliorate a pre-neoplasticcondition, selected from the group consisting of: hyperplasia (e.g.,endometrial hyperplasia and/or as described in the section entitled“Hyperproliferative Disorders”), metaplasia (e.g., connective tissuemetaplasia, atypical metaplasia, and/or as described in the sectionentitled “Hyperproliferative Disorders”), and/or dysplasia (e.g.,cervical dysplasia, and bronchopulmonary dysplasia).

In another specific embodiment, a protein, nucleic acid, or antibody ofthe invention (or fragment or variant thereof) having a “Cancer”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a benigndysproliferative disorder selected from the group consisting of: benigntumors, fibrocystic conditions, tissue hypertrophy, and/or as describedin the section entitled “Hyperproliferative Disorders”.

The recitation of “Immune/Hematopoietic” in the “Preferred Indication”column indicates that the corresponding nucleic acid and protein, orantibody against the same, of the invention (or fragment or variantthereof), may be used for example, to diagnose, treat, prevent, and/orameliorate diseases and/or disorders relating to neoplastic diseases(e.g., as described below under “Hyperproliferative Disorders”), blooddisorders (e.g., as described below under “Immune Activity”“Cardiovascular Disorders” and/or “Blood-Related Disorders”), andinfections (e.g., as described below under “Infectious Disease”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having the“Immune/Hematopoietic” recitation in the “Preferred Indication” columnof Table 1D, may be used for example, to diagnose, treat, prevent,and/or ameliorate a disease or disorder selected from the groupconsisting of: anemia, pancytopenia, leukopenia, thrombocytopenia,leukemias, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocyticanemia (ALL), plasmacytomas, multiple myeloma, Burkitt's lymphoma,arthritis, asthma, AIDS, autoimmune disease, rheumatoid arthritis,granulomatous disease, immune deficiency, inflammatory bowel disease,sepsis, neutropenia, neutrophilia, psoriasis, immune reactions totransplanted organs and tissues, systemic lupus erythematosis,hemophilia, hypercoagulation, diabetes mellitus, endocarditis,meningitis, Lyme Disease, and allergies.

The recitation of “Reproductive” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe reproductive system (e.g., as described below under “ReproductiveSystem Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Reproductive”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cryptorchism,prostatitis, inguinal hernia, varicocele, leydig cell tumors, verrucouscarcinoma, prostatitis, malacoplakia, Peyronie's disease, penilecarcinoma, squamous cell hyperplasia, dysmenorrhea, ovarianadenocarcinoma, Turner's syndrome, mucopurulent cervicitis,Sertoli-leydig tumors, ovarian cancer, uterine cancer, pelvicinflammatory disease, testicular cancer, prostate cancer, Klinefelter'ssyndrome, Young's syndrome, premature ejaculation, diabetes mellitus,cystic fibrosis, Kartagener's syndrome, testicular atrophy, testicularfeminization, anorchia, ectopic testis, epididymitis, orchitis,gonorrhea, syphilis, testicular torsion, vasitis nodosa, germ celltumors, stromal tumors, dysmenorrhea, retroverted uterus, endometriosis,fibroids, adenomyosis, anovulatory bleeding, amenorrhea, Cushing'ssyndrome, hydatidiform moles, Asherman's syndrome, premature menopause,precocious puberty, uterine polyps, dysfunctional uterine bleeding,cervicitis, chronic cervicitis, mucopurulent cervicitis, cervicaldysplasia, cervical polyps, Nabothian cysts, cervical erosion, cervicalincompetence, cervical neoplasms, pseudohermaphroditism, andpremenstrual syndrome.

The recitation of “Musculoskeletal” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe immune system (e.g., as described below under “Immune Activity”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Musculoskeletal”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: bone cancers (e.g.,osteochondromas, benign chondromas, chondroblastoma, chondromyxoidfibromas, osteoid osteomas, giant cell tumors, multiple myeloma,osteosarcomas), Paget's Disease, rheumatoid arthritis, systemic lupuserythematosus, osteomyelitis, Lyme Disease, gout, bursitis, tendonitis,osteoporosis, osteoarthritis, muscular dystrophy, mitochondrialmyopathy, cachexia, and multiple sclerosis.

The recitation of “Cardiovascular” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe cardiovascular system (e.g., as described below under“Cardiovascular Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cardiovascular”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: myxomas, fibromas,rhabdomyomas, cardiovascular abnormalities (e.g., congenital heartdefects, cerebral arteriovenous malformations, septal defects), heartdisease (e.g., heart failure, congestive heart disease, arrhythmia,tachycardia, fibrillation, pericardial Disease, endocarditis), cardiacarrest, heart valve disease (e.g., stenosis, regurgitation, prolapse),vascular disease (e.g., hypertension, coronary artery disease, angina,aneurysm, arteriosclerosis, peripheral vascular disease), hyponatremia,hypernatremia, hypokalemia, and hyperkalemia.

The recitation of “Mixed Fetal” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Mixed Fetal”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: spina bifida,hydranencephaly, neurofibromatosis, fetal alcohol syndrome, diabetesmellitus, PKU, Down's syndrome, Patau syndrome, Edwards syndrome, Turnersyndrome, Apert syndrome, Carpenter syndrome, Conradi syndrome, Crouzonsyndrome, cutis laxa, Cornelia de Lange syndrome, Ellis-van Creveldsyndrome, Holt-Oram syndrome, Kartagener syndrome, Meckel-Grubersyndrome, Noonan syndrome, Pallister-Hall syndrome, Rubinstein-Taybisyndrome, Scimitar syndrome, Smith-Lemli-Opitz syndrome,thromocytopenia-absent radius (TAR) syndrome, Treacher Collins syndrome,Williams syndrome, Hirschsprung's disease, Meckel's diverticulum,polycystic kidney disease, Turner's syndrome, and gonadal dysgenesis,Klippel-Feil syndrome, Ostogenesis imperfecta, muscular dystrophy,Tay-Sachs disease, Wilm's tumor, neuroblastoma, and retinoblastoma.

The recitation of “Excretory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and renaldisorders (e.g., as described below under “Renal Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Excretory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: bladder cancer, prostatecancer, benign prostatic hyperplasia, bladder disorders (e.g., urinaryincontinence, urinary retention, urinary obstruction, urinary tractInfections, interstitial cystitis, prostatitis, neurogenic bladder,hematuria), renal disorders (e.g., hydronephrosis, proteinuria, renalfailure, pyelonephritis, urolithiasis, reflux nephropathy, andunilateral obstructive uropathy).

The recitation of “Neural/Sensory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the nervous system (e.g., as described below under “NeuralActivity and Neurological Diseases”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Neural/Sensory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: brain cancer (e.g.,brain stem glioma, brain tumors, central nervous system (Primary)lymphoma, central nervous system lymphoma, cerebellar astrocytoma, andcerebral astrocytoma, neurodegenerative disorders (e.g., Alzheimer'sDisease, Creutzfeldt-Jakob Disease, Parkinson's Disease, and IdiopathicPresenile Dementia), encephalomyelitis, cerebral malaria, meningitis,metabolic brain diseases (e.g., phenylketonuria and pyruvate carboxylasedeficiency), cerebellar ataxia, ataxia telangiectasia, and AIDS DementiaComplex, schizophrenia, attention deficit disorder, hyperactiveattention deficit disorder, autism, and obsessive compulsive disorders.

The recitation of “Respiratory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the respiratory system (e.g., as described below under“Respiratory Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Respiratory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cancers of therespiratory system such as larynx cancer, pharynx cancer, tracheacancer, epiglottis cancer, lung cancer, squamous cell carcinomas, smallcell (oat cell) carcinomas, large cell carcinomas, and adenocarcinomas.Allergic reactions, cystic fibrosis, sarcoidosis, histiocytosis X,infiltrative lung diseases (e.g., pulmonary fibrosis and lymphoidinterstitial pneumonia), obstructive airway diseases (e.g., asthma,emphysema, chronic or acute bronchitis), occupational lung diseases(e.g., silicosis and asbestosis), pneumonia, and pleurisy.

The recitation of “Endocrine” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the respiratory system (e.g., as described below under“Respiratory Disorders”), renal disorders (e.g., as described belowunder “Renal Disorders”), and disorders of the endocrine system (e.g.,as described below under “Endocrine Disorders”.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having an “Endocrine”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cancers of endocrinetissues and organs (e.g., cancers of the hypothalamus, pituitary gland,thyroid gland, parathyroid glands, pancreas, adrenal glands, ovaries,and testes), diabetes (e.g., diabetes insipidus, type I and type IIdiabetes mellitus), obesity, disorders related to pituitary glands(e.g., hyperpituitarism, hypopituitarism, and pituitary dwarfism),hypothyroidism, hyperthyroidism, goiter, reproductive disorders (e.g.male and female infertility), disorders related to adrenal glands (e.g.,Addison's Disease, corticosteroid deficiency, and Cushing's Syndrome),kidney cancer (e.g., hypemephroma, transitional cell cancer, and Wilm'stumor), diabetic nephropathy, interstitial nephritis, polycystic kidneydisease, glomerulonephritis (e.g., IgM mesangial proliferativeglomerulonephritis and glomerulonephritis caused by autoimmunedisorders; such as Goodpasture's syndrome), and nephrocalcinosis.

The recitation of “Digestive” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the gastrointestinal system (e.g., as described below under“Gastrointestinal Disorders”.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Digestive”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: ulcerative colitis,appendicitis, Crohn's disease, hepatitis, hepatic encephalopathy, portalhypertension, cholelithiasis, cancer of the digestive system (e.g.,biliary tract cancer, stomach cancer, colon cancer, gastric cancer,pancreatic cancer, cancer of the bile duct, tumors of the colon (e.g.,polyps or cancers), and cirrhosis), pancreatitis, ulcerative disease,pyloric stenosis, gastroenteritis, gastritis, gastric atropy, benigntumors of the duodenum, distension, irritable bowel syndrome,malabsorption, congenital disorders of the small intestine, bacterialand parasitic infection, megacolon, Hirschsprung's disease, aganglionicmegacolon, acquired megacolon, colitis, anorectal disorders (e.g., analfistulas, hemorrhoids), congenital disorders of the liver (e.g.,Wilson's disease, hemochromatosis, cystic fibrosis, biliary atresia, andalpha1-antitrypsin deficiency), portal hypertension, cholelithiasis, andjaundice.

The recitation of “Connective/Epithelial” in the “Preferred Indication”column indicates that the corresponding nucleic acid and protein, orantibody against the same, of the invention (or fragment or variantthereof), may be used for example, to diagnose, treat, prevent, and/orameliorate diseases and/or disorders relating to neoplastic diseases(e.g., as described below under “Hyperproliferative Disorders”),cellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), angiogenesis (e.g., as describedbelow under “Anti-Angiogenesis Activity”), and or to promote or inhibitregeneration (e.g., as described below under “Regeneration”), and woundhealing (e.g., as described below under “Wound Healing and EpithelialCell Proliferation”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a“Connective/Epithelial” recitation in the “Preferred Indication” columnof Table 1D, may be used for example, to diagnose, treat, prevent,and/or ameliorate a disease or disorder selected from the groupconsisting of: connective tissue metaplasia, mixed connective tissuedisease, focal epithelial hyperplasia, epithelial metaplasia,mucoepithelial dysplasia, graft v. host disease, polymyositis, cystichyperplasia, cerebral dysplasia, tissue hypertrophy, Alzheimer'sdisease, lymphoproliferative disorder, Waldenstron's macroglobulinemia,Crohn's disease, pernicious anemia, idiopathic Addison's disease,glomerulonephritis, bullous pemphigoid, Sjogren's syndrome, diabetesmellitus, cystic fibrosis, osteoblastoma, osteoclastoma, osteosarcoma,chondrosarcoma, osteoporosis, osteocarthritis, periodontal disease,wound healing, relapsing polychondritis, vasculitis, polyarteritisnodosa, Wegener's granulomatosis, cellulitis, rheumatoid arthritis,psoriatic arthritis, discoid lupus erythematosus, systemic lupuserythematosus, scleroderma, CREST syndrome, Sjogren's syndrome,polymyositis, dermatomyositis, mixed connective tissue disease,relapsing polychondritis, vasculitis, Henoch-Schonlein syndrome,erythema nodosum, polyarteritis nodosa, temporal (giant cell) arteritis,Takayasu's arteritis, Wegener's granulomatosis, Reiter's syndrome,Behcet's syndrome, ankylosing spondylitis, cellulitis, keloids, EhlerDanlos syndrome, Marfan syndrome, pseudoxantoma elasticum, osteogeneseimperfecta, chondysplasias, epidermolysis bullosa, Alport syndrome, andcutis laxa. TABLE 1D Gene No. cDNA Clone ID Preferred IndicationIdentifiers 1 H6BSF56 Cancer 2 H6EDM64 Cancer 3 H6EEC72 Cancer 4 HACAB68Connective/Epithelial, Immune/Hematopoietic 5 HACBJ56 Cancer 6 HACBS22Cancer 7 HADDE71 Cancer 8 HADDJ13 Connective/Epithelial 9 HADMB15 Cancer10 HAGBQ12 Excretory, Neural/Sensory 11 HAGDW20 Neural/Sensory,Reproductive 12 HAGEG10 Cancer 13 HAGEQ79 Digestive, Neural/Sensory 14HAGFS57 Cancer 15 HAGHN57 Cancer 16 HAHEA15 Cardiovascular 17 HAJAA47Immune/Hematopoietic 18 HAJAY92 Cancer 19 HAJBV67 Cancer 20 HAJCH70Cancer 21 HAOAG15 Cancer 22 HAQAI92 Digestive, Mixed Fetal, Reproductive23 HAQCE11 Reproductive 24 HATBI94 Cancer 25 HATCB45 Cancer 26 HATCD80Endocrine, Reproductive 27 HATCI03 Endocrine, Immune/Hematopoietic,Neural/Sensory 28 HATEH20 Cancer 29 HBAGD86 Cancer 30 HBCJL35 Cancer 31HBDAB91 Immune/Hematopoietic 32 HBDAB91 Immune/Hematopoietic 33 HBGBC29Cancer 34 HBGNC72 Cancer 35 HBHAA05 Neural/Sensory 36 HBHAA81 Cancer 37HBIAA59 Cancer 38 HBIAC29 Cancer 39 HBICW51 Digestive,Immune/Hematopoietic, Neural/Sensory 40 HBJAB02 Cancer 41 HBJAC65 Cancer42 HBJBM12 Immune/Hematopoietic 43 HBJCR46 Cancer 44 HBJDS79 Cancer 45HBJDW56 Immune/Hematopoietic 46 HBJEL16 Cancer 47 HBJFK45Immune/Hematopoietic 48 HBJIG20 Cancer 49 HBJKD16 Cancer 50 HBMBM96Digestive, Immune/Hematopoietic, Neural/Sensory 51 HBMBX01 Cancer 52HBMTM11 Cancer 53 HBMTX26 Immune/Hematopoietic 54 HBMTY48Immune/Hematopoietic, Reproductive 55 HBMUH74 Cardiovascular,Immune/Hematopoietic, Reproductive 56 HBMWE61 Immune/Hematopoietic 57HBNAX40 Cancer 58 HBNBJ76 Cancer 59 HBQAB79 Neural/Sensory 60 HBQAC57Neural/Sensory 61 HBSAK32 Mixed Fetal, Musculoskeletal, Neural/Sensory62 HBXCM66 Cardiovascular, Neural/Sensory, Reproductive 63 HBXCX15Immune/Hematopoietic, Neural/Sensory 64 HCDCY76 Cancer 65 HCDDL48Musculoskeletal 66 HCE1G78 Cancer 67 HCE2H52 Cancer 68 HCE3B04Digestive, Neural/Sensory 69 HCE5F78 Immune/Hematopoietic,Neural/Sensory 70 HCEDR26 Digestive, Immune/Hematopoietic,Neural/Sensory 71 HCEEE79 Neural/Sensory 72 HCEEQ25 Mixed Fetal,Neural/Sensory 73 HCEEU18 Neural/Sensory 74 HCEFZ82 Cancer 75 HCEGX05Cancer 76 HCFLN88 Cancer 77 HCFLT90 Cancer 78 HCHAB84 Cancer 79 HCMSX51Cancer 80 HCNCO11 Digestive 81 HCNSD29 Cardiovascular, Digestive,Immune/Hematopoietic 82 HCQBH72 Digestive, Excretory,Immune/Hematopoietic 83 HCQCC96 Cancer 84 HCQCJ56 Cardiovascular,Digestive, Reproductive 85 HCQCM24 Cancer 86 HCRAY10 Cancer 87 HCRBF72Cancer 88 HCRNF78 Cancer 89 HCUAF85 Immune/Hematopoietic 90 HCUCF89Immune/Hematopoietic 91 HCUCK44 Cancer 92 HCUDD64 Cancer 93 HCWAE64Immune/Hematopoietic 94 HCWFU39 Immune/Hematopoietic, Neural/Sensory 95HCWUL09 Immune/Hematopoietic, Neural/Sensory 96 HDHAA42 Cancer 97HDHEB76 Mixed Fetal, Neural/Sensory 98 HDPCW16 Cancer 99 HDPDI72Immune/Hematopoietic 100 HDPDJ58 Cancer 101 HDPFF10 Cancer 102 HDPFU43Cancer 103 HDPFY18 Cancer 104 HDPGE24 Cancer 105 HDPIU94 Cancer 106HDPOC24 Cancer 107 HDPOL37 Immune/Hematopoietic, Reproductive 108HDPOO76 Cancer 109 HDPPD93 Cancer 110 HDPPQ30 Connective/Epithelial,Immune/Hematopoietic, Musculoskeletal 111 HDPPW82 Immune/Hematopoietic112 HDPXN20 Immune/Hematopoietic 113 HDQHM36 Immune/Hematopoietic 114HDTAU35 Immune/Hematopoietic 115 HDTAV54 Cancer 116 HDTFX18Immune/Hematopoietic, Reproductive 117 HDTGW48 Immune/Hematopoietic,Reproductive 118 HDTLM18 Immune/Hematopoietic 119 HE2CA60 Cancer 120HE2CA60 Cancer 121 HE2CH58 Digestive, Mixed Fetal 122 HE2CM39 Cancer 123HE2HC60 Cancer 124 HE2PO93 Cancer 125 HE6AU52 Mixed Fetal 126 HE6CS65Cancer 127 HE6DO92 Immune/Hematopoietic, Mixed Fetal 128 HE6EY13 Cancer129 HE6FU11 Mixed Fetal, Neural/Sensory, Respiratory 130 HE6FV29 Cancer131 HE8FC45 Cancer 132 HE8FC45 Cancer 133 HE8FD92 Cancer 134 HE8FD92Cancer 135 HE8FD92 Cancer 136 HE8FD92 Cancer 137 HE8FD92 Cancer 138HE8SG96 Mixed Fetal, Neural/Sensory 139 HE8TY46 Cancer 140 HE9CY05 MixedFetal 141 HE9EA10 Cancer 142 HE9GG20 Cancer 143 HEBCI18 Cancer 144HEBCY54 Cancer 145 HEBDF77 Neural/Sensory 146 HEBDQ91 Neural/Sensory 147HEBFR46 Cancer 148 HEBGE07 Neural/Sensory 149 HEGAU15 Excretory,Immune/Hematopoietic, Reproductive 150 HELAT35 Cardiovascular, MixedFetal 151 HELBU54 Cardiovascular, Digestive 152 HELGG84 Cancer 153HELGG84 Cancer 154 HEMEY47 Cancer 155 HEOMC46 Immune/Hematopoietic 156HEPBA14 Reproductive 157 HEQAH80 Cancer 158 HEQBF89 Reproductive 159HETCI16 Cancer 160 HETDW58 Cancer 161 HETEY67 Connective/Epithelial,Immune/Hematopoietic, Reproductive 162 HFCDW95 Cancer 163 HFCEI04Neural/Sensory 164 HFCFD04 Neural/Sensory 165 HFCFE20 Cancer 166 HFEAY59Connective/Epithelial 167 HFGAJ16 Cancer 168 HFIHZ75 Cancer 169 HFIJA29Cancer 170 HFIJA68 Musculoskeletal 171 HFKES05 Cancer 172 HFKEU12Excretory 173 HFPCZ55 Cancer 174 HFPDR62 Immune/Hematopoietic,Neural/Sensory 175 HFPDS07 Cancer 176 HFRAB10 Excretory,Immune/Hematopoietic, Neural/Sensory 177 HFTBM38 Cancer 178 HFTDH56Cancer 179 HFVGK35 Cancer 180 HFVHW43 Digestive 181 HFXAV37Immune/Hematopoietic, Neural/Sensory 182 HFXBN86 Neural/Sensory 183HFXBT66 Neural/Sensory 184 HFXFZ46 Neural/Sensory 185 HGBER72 Cancer 186HGBEY14 Cancer 187 HGBGN34 Cancer 188 HGBHP91 Digestive 189 HGCAC19Cancer 190 HGCAC19 Cancer 191 HGCAC19 Cancer 192 HHEAK45 Cancer 193HHEGS55 Immune/Hematopoietic 194 HHEOW19 Cancer 195 HHFFF87 Cancer 196HHFFL34 Cancer 197 HHFFS40 Cancer 198 HHGCS78 Immune/Hematopoietic 199HHGDT26 Immune/Hematopoietic, Reproductive 200 HHPFU28 Cancer 201HHPSA85 Cancer 202 HHSBI06 Cancer 203 HHSBI65 Cancer 204 HHSDI53 Cancer205 HHSFC09 Cancer 206 HHSGL28 Cancer 207 HILCA24 Digestive,Immune/Hematopoietic, Reproductive 208 HILCA24 Digestive,Immune/Hematopoietic, Reproductive 209 HISAT67 Cancer 210 HJBCU75 Cancer211 HJMAA03 Cancer 212 HJMAV41 Cancer 213 HJMAY90 Cancer 214 HJPBE39Cancer 215 HJPBK28 Cancer 216 HJPCH08 Cancer 217 HKABU43 Cancer 218HKACI79 Cancer 219 HKAFF50 Cancer 220 HKGBF25 Cancer 221 HKIXC44 Cancer222 HKMLK03 Digestive, Excretory, Immune/Hematopoietic 223 HKMLM95Cancer 224 HKTAB41 Digestive, Excretory 225 HLDBG17 Cancer 226 HLDCA54Cancer 227 HLDQU79 Cancer 228 HLDRT09 Cancer 229 HLHAP05Immune/Hematopoietic, Neural/Sensory, Respiratory 230 HLHCS23Respiratory 231 HLIBO72 Cancer 232 HLICE88 Cancer 233 HLICO10 Cancer 234HLJBS28 Cancer 235 HLMBW89 Cancer 236 HLMGP50 Digestive,Immune/Hematopoietic 237 HLMJB64 Cancer 238 HLMMX62 Cancer 239 HLQAS12Cancer 240 HLQCL64 Digestive, Immune/Hematopoietic, Reproductive 241HLQCX36 Digestive 242 HLWAF06 Immune/Hematopoietic, Reproductive 243HLWAU42 Cancer 244 HLWAU42 Cancer 245 HLWAV47 Cancer 246 HLWBB73 Cancer247 HLWCN37 Cancer 248 HLWDB73 Cancer 249 HLYDF73 Immune/Hematopoietic250 HLYEU59 Immune/Hematopoietic 251 HLYGB19 Cancer 252 HLYGE16 Cancer253 HLYGY91 Cancer 254 HMCAZ04 Cancer 255 HMCAZ04 Cancer 256 HMCAZ04Cancer 257 HMCAZ04 Cancer 258 HMCAZ04 Cancer 259 HMCFH60 Cancer 260HMDAB29 Digestive, Neural/Sensory 261 HMDAD44 Connective/Epithelial,Immune/Hematopoietic, Neural/Sensory 262 HMEBB82 Cancer 263 HMEDE24Cardiovascular 264 HMEDI90 Cardiovascular, Musculoskeletal,Neural/Sensory 265 HMELM75 Cancer 266 HMIAK10 Neural/Sensory 267 HMIBF07Neural/Sensory 268 HMICI80 Cardiovascular, Endocrine, Neural/Sensory 269HMICP65 Cancer 270 HMJAK70 Neural/Sensory 271 HMSBE04Immune/Hematopoietic 272 HMSCL38 Immune/Hematopoietic, Neural/Sensory273 HMSCR69 Cancer 274 HMSHC86 Immune/Hematopoietic 275 HMSHU20Immune/Hematopoietic, Reproductive 276 HMSHY25 Immune/Hematopoietic 277HMTAB77 Cancer 278 HMUAE26 Cancer 279 HMUAN45 Cancer 280 HMVBC31 Cancer281 HMVDU15 Cancer 282 HMWBL03 Cancer 283 HMWJF53 Cancer 284 HNEAK81Immune/Hematopoietic 285 HNECL22 Cancer 286 HNECW49 Immune/Hematopoietic287 HNEDH88 Immune/Hematopoietic 288 HNFAC50 Cancer 289 HNFGR08Immune/Hematopoietic 290 HNFHF34 Cancer 291 HNGAK51 Immune/Hematopoietic292 HNGAM58 Immune/Hematopoietic 293 HNGBH53 Immune/Hematopoietic 294HNGDQ38 Immune/Hematopoietic 295 HNGDX18 Cancer 296 HNGDY34Immune/Hematopoietic 297 HNGEA34 Digestive, Immune/Hematopoietic 298HNGEQ75 Immune/Hematopoietic, Neural/Sensory 299 HNGGA68Immune/Hematopoietic, Musculoskeletal 300 HNGGP65 Immune/Hematopoietic301 HNGHZ69 Immune/Hematopoietic 302 HNGIV64 Immune/Hematopoietic 303HNGJB41 Immune/Hematopoietic 304 HNGKT41 Immune/Hematopoietic 305HNGMW45 Immune/Hematopoietic 306 HNGNK44 Immune/Hematopoietic 307HNGNO53 Immune/Hematopoietic 308 HNGPJ25 Immune/Hematopoietic, MixedFetal, Musculoskeletal 309 HNHEN82 Cancer 310 HNHFE71Immune/Hematopoietic 311 HNHGK22 Immune/Hematopoietic 312 HNHHB10Immune/Hematopoietic, Reproductive 313 HNHKS19 Immune/Hematopoietic,Reproductive 314 HNTBT17 Cancer 315 HNTMH79 Cancer 316 HOABP31 Cancer317 HOABP31 Cancer 318 HOACG07 Cancer 319 HODAG07 Reproductive 320HODBB70 Reproductive 321 HODBV05 Cancer 322 HODCZ32 Reproductive 323HOEBK60 Cancer 324 HOFAA78 Cancer 325 HOFNB74 Reproductive 326 HOFNU55Reproductive 327 HOGBF01 Reproductive 328 HORBS82 Cancer 329 HORBV76Immune/Hematopoietic, Reproductive 330 HOSDO75 Cancer 331 HOSEC25Musculoskeletal 332 HOSEI81 Digestive, Musculoskeletal 333 HOSEJ94Cancer 334 HOUCA21 Connective/Epithelial, Immune/Hematopoietic,Musculoskeletal 335 HOUDE92 Cancer 336 HOUDR07 Cancer 337 HOUED72Connective/Epithelial 338 HOUFS04 Cancer 339 HOUHI25 Cancer 340 HOVBD85Musculoskeletal, Reproductive 341 HPCAB41 Immune/Hematopoietic,Reproductive 342 HPCAL26 Cancer 343 HPEAD23 Cancer 344 HPFBA54Reproductive 345 HPFCI36 Cancer 346 HPFDI37 Cancer 347 HPIAA80 Cancer348 HPJBJ51 Immune/Hematopoietic, Reproductive 349 HPJBJ51Immune/Hematopoietic, Reproductive 350 HPJBU43 Reproductive 351 HPJCW58Reproductive 352 HPMBX22 Cancer 353 HPMCJ84 Reproductive 354 HPMCV30Cancer 355 HPMFH77 Cancer 356 HPQAX38 Cardiovascular 357 HPQAX38Cardiovascular 358 HPQCB83 Cancer 359 HPQCC53 Cancer 360 HPRBH85 Cancer361 HPRCA64 Cancer 362 HPRCD35 Cancer 363 HPTRM02 Cancer 364 HPWBA29Reproductive 365 HPWDK06 Cancer 366 HRAAD30 Cancer 367 HRADA42 Cancer368 HRADF49 Cancer 369 HRADN25 Cancer 370 HRADT25 Digestive, Excretory371 HRDAI17 Cancer 372 HRDDQ39 Cancer 373 HRDER22 Cancer 374 HRDEX93Cancer 375 HRDFK37 Cancer 376 HRGBD54 Cancer 377 HROEA08 Cancer 378HSAVA08 Immune/Hematopoietic 379 HSAVW42 Cancer 380 HSAWN53Immune/Hematopoietic 381 HSAWZ40 Immune/Hematopoietic 382 HSAYC41Excretory, Immune/Hematopoietic, Reproductive 383 HSDZM54 Neural/Sensory384 HSHBF76 Cancer 385 HSIFG47 Digestive 386 HSJBY32Immune/Hematopoietic, Musculoskeletal, Neural/Sensory 387 HSKDR27 Cancer388 HSLHG78 Cancer 389 HSLHX15 Musculoskeletal 390 HSNAP85 Cancer 391HSNAZ09 Cancer 392 HSNBM34 Cancer 393 HSOAH16 Digestive 394 HSQBF66Cancer 395 HSQDO85 Cancer 396 HSQES57 Cancer 397 HSRBE06 Cancer 398HSSDI26 Musculoskeletal 399 HSSEA64 Cancer 400 HSSEF77 Cancer 401HSSFE38 Cancer 402 HSSGJ58 Musculoskeletal 403 HSWBE76 Cancer 404HSXCP38 Cardiovascular, Neural/Sensory 405 HSYBI06 Cancer 406 HT1SC27Digestive, Immune/Hematopoietic, Reproductive 407 HT3BF49Immune/Hematopoietic 408 HT4FV41 Cancer 409 HT5FX79 Cancer 410 HT5GR59Cancer 411 HTAEI78 Immune/Hematopoietic 412 HTDAA78 Immune/Hematopoietic413 HTEAG62 Digestive, Immune/Hematopoietic, Reproductive 414 HTECB02Cancer 415 HTECC15 Cancer 416 HTEDF18 Reproductive 417 HTEDJ28 Cancer418 HTEDS12 Cardiovascular, Immune/Hematopoietic, Reproductive 419HTEED26 Reproductive 420 HTEED26 Reproductive 421 HTEEF26 Cancer 422HTEEF26 Cancer 423 HTEEW69 Reproductive 424 HTEGS07 Reproductive 425HTEGS11 Cancer 426 HTEHA56 Cancer 427 HTEHU59 Cancer 428 HTEJD29Reproductive 429 HTEKM46 Cancer 430 HTEMQ17 Cancer 431 HTENR63 Cancer432 HTGGM44 Cancer 433 HTHBZ06 Cancer 434 HTLAP64 Cancer 435 HTLBT80Cancer 436 HTLDA84 Reproductive 437 HTLDN29 Cancer 438 HTLDU78Reproductive 439 HTLEC82 Cancer 440 HTLEM16 Cancer 441 HTLEV48Reproductive 442 HTLFA13 Musculoskeletal, Reproductive 443 HTLFI73Digestive, Immune/Hematopoietic, Reproductive 444 HTLGI89 Cancer 445HTLIF11 Cancer 446 HTLIF12 Excretory, Reproductive 447 HTLIF12Excretory, Reproductive 448 HTLIF12 Excretory, Reproductive 449 HTLIF12Excretory, Reproductive 450 HTLIF12 Excretory, Reproductive 451 HTLIF12Excretory, Reproductive 452 HTNAM63 Endocrine 453 HTNBK13 Cancer 454HTOAI50 Digestive, Immune/Hematopoietic 455 HTOAM11Immune/Hematopoietic, Neural/Sensory 456 HTODH57 Immune/Hematopoietic457 HTODH83 Immune/Hematopoietic 458 HTOEV16 Cancer 459 HTOGR38Immune/Hematopoietic 460 HTOHO21 Immune/Hematopoietic 461 HTOHQ05Immune/Hematopoietic 462 HTOJL95 Cancer 463 HTOJL95 Cancer 464 HTPDU17Cancer 465 HTSFJ32 Immune/Hematopoietic 466 HTTCB60 Cancer 467 HTTEE41Cancer 468 HTTEZ02 Cancer 469 HTWEH94 Immune/Hematopoietic 470 HTXBD09Cancer 471 HTXDB22 Cancer 472 HTXDC38 Cancer 473 HTXDC77 Cancer 474HTXDD61 Cancer 475 HTXDG92 Cancer 476 HTXET11 Digestive,Immune/Hematopoietic 477 HTXFA72 Immune/Hematopoietic 478 HTXJY08 Cancer479 HTXKF95 Cancer 480 HTXMZ07 Cancer 481 HUFCL31 Digestive,Immune/Hematopoietic 482 HUKBT67 Cancer 483 HUKDF20 Cardiovascular,Neural/Sensory, Reproductive 484 HUKDY82 Cancer 485 HUSCJ14 Cancer 486HUSGL67 Cancer 487 HUSGU40 Cancer 488 HUSIR18 Cancer 489 HUVDJ48Digestive, Reproductive 490 HWAAI12 Cancer 491 HWBBQ70Immune/Hematopoietic, Neural/Sensory 492 HWBCN36 Immune/Hematopoietic493 HWBDJ08 Cancer 494 HWBFX16 Immune/Hematopoietic 495 HWDAC26Connective/Epithelial, Immune/Hematopoietic, Neural/Sensory 496 HWDAG96Cancer 497 HWDAJ01 Connective/Epithelial 498 HWHPB78 Cancer 499 HYABC84Cancer 500 HYABC84 Cancer 501 H2CBD20 Digestive 502 H2CBH91 Cancer 503H2LBA54 Cancer 504 H2LBB09 Cancer 505 H2LBB09 Cancer 506 H2MAC63Digestive, Reproductive 507 H2MBA76 Cancer 508 H2MBF60 Cancer 509H6BSM88 Cancer 510 H6EEA48 Cancer 511 H6EEN71 Cancer 512 H6EEO05 Cancer513 H6EEU40 Cancer 514 H7TDB54 Cancer 515 H7TMB95 Cancer 516 HAAAT06Cancer 517 HACAD42 Connective/Epithelial, Mixed Fetal, Neural/Sensory518 HACBJ11 Cancer 519 HACBS86 Cancer 520 HACBT91 Cancer 521 HACBZ73Cancer 522 HACCK29 Connective/Epithelial 523 HADAB60 Cancer 524 HADAM31Connective/Epithelial 525 HADCL19 Connective/Epithelial 526 HADCZ65Connective/Epithelial, Immune/Hematopoietic 527 HADDC04Connective/Epithelial, Reproductive 528 HADDP23 Cancer 529 HADDP51Cancer 530 HADDR24 Cancer 531 HADET62 Connective/Epithelial 532 HADEY08Cancer 533 HADEY22 Connective/Epithelial 534 HADEY22Connective/Epithelial 535 HADFB84 Cancer 536 HADFD01 Cancer 537 HADFD10Cancer 538 HADFK11 Connective/Epithelial 539 HADFT44Connective/Epithelial, Mixed Fetal, Neural/Sensory 540 HADFW20Connective/Epithelial 541 HADFX10 Connective/Epithelial, Neural/Sensory542 HADFY80 Connective/Epithelial, Digestive 543 HADGD93 Cardiovascular,Connective/Epithelial 544 HADMA77 Cancer 545 HADXA10 Cancer 546 HADXA10Cancer 547 HAFBB15 Cancer 548 HAFBL14 Cancer 549 HAGAB62 Cancer 550HAGAB83 Neural/Sensory 551 HAGAE84 Neural/Sensory 552 HAGAF75 Digestive,Neural/Sensory 553 HAGAK40 Cancer 554 HAGAU43 Neural/Sensory 555 HAGAZ36Neural/Sensory 556 HAGBC57 Cancer 557 HAGBL31 Neural/Sensory 558 HAGBO09Mixed Fetal, Neural/Sensory 559 HAGBO12 Neural/Sensory 560 HAGBO51Neural/Sensory 561 HAGBS89 Immune/Hematopoietic, Musculoskeletal,Neural/Sensory 562 HAGBV06 Cancer 563 HAGBV25 Cancer 564 HAGBV29Immune/Hematopoietic, Neural/Sensory 565 HAGCC87 Digestive,Immune/Hematopoietic, Neural/Sensory 566 HAGCH67 Neural/Sensory 567HAGCI69 Neural/Sensory, Reproductive 568 HAGCT33 Immune/Hematopoietic,Mixed Fetal, Neural/Sensory 569 HAGCZ70 Neural/Sensory 570 HAGDC73Cancer 571 HAGDG84 Immune/Hematopoietic, Neural/Sensory 572 HAGDH85Neural/Sensory 573 HAGDI69 Neural/Sensory 574 HAGDJ53Immune/Hematopoietic, Neural/Sensory 575 HAGDJ56 Cardiovascular,Endocrine, Neural/Sensory 576 HAGDL51 Immune/Hematopoietic,Musculoskeletal, Neural/Sensory 577 HAGDO70 Cancer 578 HAGDT30 Cancer579 HAGDW68 Endocrine, Neural/Sensory 580 HAGDX84 Cancer 581 HAGEK37Cancer 582 HAGEK86 Cancer 583 HAGEP30 Neural/Sensory 584 HAGEQ58Neural/Sensory 585 HAGEQ67 Cancer 586 HAGEU26 Neural/Sensory 587 HAGEW83Neural/Sensory 588 HAGEX49 Cancer 589 HAGEX49 Cancer 590 HAGFD75 Cancer591 HAGFF43 Cancer 592 HAGFJ67 Digestive, Immune/Hematopoietic,Neural/Sensory 593 HAGFM58 Cardiovascular, Neural/Sensory 594 HAGFT48Cancer 595 HAGFU31 Neural/Sensory 596 HAGFW13 Neural/Sensory 597 HAGHE85Cardiovascular, Neural/Sensory 598 HAGHR18 Neural/Sensory 599 HAGIB90Cancer 600 HAHEM51 Cardiovascular 601 HAHSA76 Cardiovascular 602 HAHSD51Cancer 603 HAIBR76 Cancer 604 HAIBT20 Cancer 605 HAIBV91 Cancer 606HAICE62 Cancer 607 HAICL90 Digestive, Immune/Hematopoietic, Reproductive608 HAICV44 Cancer 609 HAIDP45 Cancer 610 HAJAB88 Cancer 611 HAJAZ56Cancer 612 HAMFC67 Cancer 613 HAMFQ38 Cancer 614 HAMGG01 Cancer 615HANGB24 Cancer 616 HANKC93 Musculoskeletal 617 HAPAD35 Cancer 618HAPBR13 Cancer 619 HAPBU09 Cancer 620 HAPBU86 Cancer 621 HAPBU86 Cancer622 HAPNJ33 Cancer 623 HAPNL62 Cancer 624 HAPNO50 Cancer 625 HAPNY10Cancer 626 HAPPW83 Cancer 627 HAPQJ73 Cancer 628 HAPQK26 Reproductive629 HAPQU71 Cancer 630 HAPQU71 Cancer 631 HAPQW18 Cancer 632 HAPQX44Cancer 633 HAPRK55 Cancer 634 HAPSH37 Cancer 635 HAQBG57 Cancer 636HAQBY85 Cancer 637 HAQBZ15 Cancer 638 HAQCE18 Immune/Hematopoietic,Reproductive 639 HAQCF94 Cancer 640 HARAE26 Neural/Sensory 641 HARAT69Cancer 642 HARAZ81 Cancer 643 HASAU26 Cancer 644 HASAX57 Cancer 645HASAY07 Cancer 646 HATAE01 Cancer 647 HATAG52 Endocrine, Neural/Sensory,Reproductive 648 HATAL05 Cancer 649 HATBA90 Endocrine 650 HATBM71Endocrine 651 HATCF80 Cancer 652 HATCI67 Cancer 653 HATCJ27 Cancer 654HATCS79 Endocrine, Immune/Hematopoietic 655 HATCX03 Cancer 656 HATDE03Cancer 657 HATDF41 Cancer 658 HATDH23 Cancer 659 HATDH55 Cancer 660HATDO84 Endocrine 661 HATDU01 Cancer 662 HATDW05 Endocrine 663 HATEF13Digestive, Endocrine 664 HATEF64 Cancer 665 HATEH40 Cancer 666 HATEI22Cancer 667 HAUCC84 Cancer 668 HAWAS41 Connective/Epithelial, Excretory,Immune/Hematopoietic 669 HAWBA65 Cancer 670 HBAGH64 Cancer 671 HBAGV01Connective/Epithelial, Excretory 672 HBAMC50 Excretory 673 HBAMC57Excretory 674 HBBBA42 Cancer 675 HBBBB08 Neural/Sensory 676 HBBBE83Cancer 677 HBBMA11 Neural/Sensory 678 HBCAK10 Digestive,Immune/Hematopoietic, Reproductive 679 HBCAK80 Cancer 680 HBCAQ48 Cancer681 HBCAY17 Cancer 682 HBCGE46 Musculoskeletal 683 HBGBA14 Cancer 684HBGBE75 Cancer 685 HBGBP22 Cancer 686 HBGFQ34 Reproductive 687 HBGML95Reproductive 688 HBGMT60 Cancer 689 HBHAA53 Neural/Sensory 690 HBIAU43Cancer 691 HBIAW58 Neural/Sensory 692 HBIBB20 Cancer 693 HBIBF26 Cancer694 HBIBM33 Neural/Sensory 695 HBIBN67 Cancer 696 HBIBQ69Immune/Hematopoietic, Neural/Sensory 697 HBIBR38 Neural/Sensory 698HBIBR61 Cancer 699 HBIBS33 Neural/Sensory 700 HBIBT13 Digestive,Immune/Hematopoietic, Neural/Sensory 701 HBIBZ20 Neural/Sensory 702HBICB80 Cancer 703 HBJAC40 Cancer 704 HBJAV56 Immune/Hematopoietic,Musculoskeletal 705 HBJAY14 Immune/Hematopoietic 706 HBJBQ69Immune/Hematopoietic 707 HBJBR40 Immune/Hematopoietic 708 HBJCH46Immune/Hematopoietic, Musculoskeletal 709 HBJCR17 Cancer 710 HBJCS26Cancer 711 HBJCW24 Cancer 712 HBJDC57 Immune/Hematopoietic, Reproductive713 HBJDR18 Immune/Hematopoietic 714 HBJDR83 Immune/Hematopoietic 715HBJEE51 Immune/Hematopoietic 716 HBJEL21 Cancer 717 HBJFH84 Cancer 718HBJFJ14 Cancer 719 HBJFJ26 Cancer 720 HBJFJ83 Immune/Hematopoietic,Mixed Fetal 721 HBJFJ83 Immune/Hematopoietic, Mixed Fetal 722 HBJFP47Immune/Hematopoietic, Reproductive 723 HBJFR77 Cancer 724 HBJFU30 Cancer725 HBJFX41 Immune/Hematopoietic 726 HBJHO83 Immune/Hematopoietic,Reproductive 727 HBJHS92 Immune/Hematopoietic, Neural/Sensory 728HBJHT01 Immune/Hematopoietic, Reproductive 729 HBJHT01Immune/Hematopoietic, Reproductive 730 HBJHW06 Immune/Hematopoietic,Reproductive 731 HBJIR14 Cancer 732 HBJJA26 Immune/Hematopoietic 733HBJJX02 Immune/Hematopoietic 734 HBJLH78 Immune/Hematopoietic 735HBJND04 Cancer 736 HBJND57 Immune/Hematopoietic 737 HBKDF66 Cancer 738HBKEA94 Cancer 739 HBKEE60 Digestive 740 HBKEI41 Endocrine, Mixed Fetal,Reproductive 741 HBMBD51 Digestive, Immune/Hematopoietic 742 HBMBD73Cancer 743 HBMBE33 Immune/Hematopoietic 744 HBMBM17Immune/Hematopoietic, Reproductive 745 HBMCL59 Immune/Hematopoietic 746HBMCM96 Immune/Hematopoietic, Neural/Sensory 747 HBMCQ74 Cancer 748HBMCQ74 Cancer 749 HBMCT40 Cancer 750 HBMDM08 Immune/Hematopoietic 751HBMSN62 Cancer 752 HBMSO30 Immune/Hematopoietic 753 HBMTM50 Cancer 754HBMUD59 Cancer 755 HBMUI10 Cancer 756 HBMUJ48 Cancer 757 HBMUR39Immune/Hematopoietic 758 HBMVF65 Endocrine, Immune/Hematopoietic,Neural/Sensory 759 HBMVF65 Endocrine, Immune/Hematopoietic,Neural/Sensory 760 HBMWC39 Cancer 761 HBMWJ92 Cancer 762 HBMWS52Immune/Hematopoietic 763 HBMXE34 Cancer 764 HBMXG01 Immune/Hematopoietic765 HBMXG76 Immune/Hematopoietic 766 HBMXM05 Excretory,Immune/Hematopoietic, Neural/Sensory 767 HBMXW83 Cancer 768 HBNAE74Excretory, Musculoskeletal, Reproductive 769 HBNAX16 Cancer 770 HBNAZ35Endocrine, Reproductive 771 HBODK40 Cancer 772 HBODV76 Cancer 773HBPAD89 Cancer 774 HBPAF39 Immune/Hematopoietic, Neural/Sensory 775HBQAC45 Neural/Sensory 776 HBQAC72 Neural/Sensory 777 HBQAE37Neural/Sensory 778 HBSAJ63 Cancer 779 HBSAJ63 Cancer 780 HBSDD24 Cancer781 HBWBD25 Immune/Hematopoietic, Neural/Sensory 782 HBXAS93Neural/Sensory 783 HBXAT27 Cancer 784 HBXAW57 Neural/Sensory 785 HBXBI29Neural/Sensory 786 HBXBM24 Neural/Sensory 787 HBXBM78 Cancer 788 HBXCD59Immune/Hematopoietic, Neural/Sensory 789 HBXCE43 Neural/Sensory 790HBXCG08 Cancer 791 HBXCM52 Cancer 792 HBXCQ03 Cancer 793 HBXCR15 Cancer794 HBXDL52 Cancer 795 HBXDL52 Cancer 796 HBXDN08 Cancer 797 HBXDN65Neural/Sensory 798 HBXFA04 Neural/Sensory 799 HBXFE64 Neural/Sensory 800HBXFI33 Immune/Hematopoietic, Neural/Sensory 801 HBXFP72 Cancer 802HBXFS31 Neural/Sensory 803 HBXFW01 Neural/Sensory 804 HBXGE12 Cancer 805HBXGL91 Neural/Sensory, Reproductive 806 HBXGM24 Cancer 807 HBZAI75Digestive, Reproductive 808 HCABP33 Cancer 809 HCABW10 Cancer 810HCACZ65 Cancer 811 HCBAB34 Cancer 812 HCDAA24 Cancer 813 HCDAA24 Cancer814 HCDAF17 Cancer 815 HCDAH02 Immune/Hematopoietic, Musculoskeletal 816HCDAP33 Cancer 817 HCDAR40 Cardiovascular, Immune/Hematopoietic,Musculoskeletal 818 HCDAS02 Cancer 819 HCDBE76 Cancer 820 HCDBO32 Cancer821 HCDBW67 Cancer 822 HCDBZ31 Musculoskeletal 823 HCDCB03 Cancer 824HCDCE51 Cancer 825 HCDCI42 Immune/Hematopoietic, Musculoskeletal 826HCDDB15 Cancer 827 HCDDX81 Musculoskeletal 828 HCDDY28 Cardiovascular,Musculoskeletal 829 HCDEB19 Cancer 830 HCDEN46 Cancer 831 HCDES69Immune/Hematopoietic, Musculoskeletal, Reproductive 832 HCE1D45 Cancer833 HCE1N56 Cancer 834 HCE1T53 Neural/Sensory 835 HCE1Y27 Digestive,Neural/Sensory, Reproductive 836 HCE1Y34 Immune/Hematopoietic,Neural/Sensory 837 HCE2B57 Musculoskeletal, Neural/Sensory 838 HCE2E47Immune/Hematopoietic, Mixed Fetal, Neural/Sensory 839 HCE2I23Neural/Sensory 840 HCE2P90 Neural/Sensory 841 HCE3A54 Neural/Sensory 842HCE3C46 Immune/Hematopoietic, Neural/Sensory 843 HCE3D58 Cancer 844HCE3D89 Endocrine, Neural/Sensory 845 HCE3J43 Cancer 846 HCE3L04Neural/Sensory 847 HCE3N23 Cancer 848 HCE3R01 Cancer 849 HCE3R01 Cancer850 HCE3R01 Cancer 851 HCE3R46 Cancer 852 HCE4H32 Cancer 853 HCE4H32Cancer 854 HCE4T64 Cancer 855 HCE4W88 Cancer 856 HCE5B62 Neural/Sensory857 HCE5H86 Cancer 858 HCE5J64 Digestive, Neural/Sensory 859 HCEBF54Cancer 860 HCECO77 Cancer 861 HCEDH42 Neural/Sensory 862 HCEDJ05Neural/Sensory 863 HCEDJ26 Cancer 864 HCEDN07 Digestive, Mixed Fetal,Neural/Sensory 865 HCEDO17 Cancer 866 HCEEG48 Neural/Sensory 867 HCEEM33Cancer 868 HCEEP16 Immune/Hematopoietic, Neural/Sensory, Reproductive869 HCEER60 Cardiovascular, Digestive, Neural/Sensory 870 HCEFA10Immune/Hematopoietic, Neural/Sensory, Reproductive 871 HCEFA50Neural/Sensory 872 HCEFA94 Neural/Sensory 873 HCEFC27 Cancer 874 HCEFG93Neural/Sensory 875 HCEFH31 Cancer 876 HCEFK56 Cancer 877 HCEFN51 Cancer878 HCEGG08 Cancer 879 HCEGH74 Cancer 880 HCEGK81 Cancer 881 HCEGS49Connective/Epithelial, Neural/Sensory, Reproductive 882 HCEGU75 Cancer883 HCEGY33 Cancer 884 HCEHW24 Neural/Sensory 885 HCEJL08 Cancer 886HCEJP93 Cancer 887 HCELB04 Cancer 888 HCEMA08 Cancer 889 HCENN67Digestive, Endocrine, Neural/Sensory 890 HCENQ22 Digestive,Immune/Hematopoietic, Neural/Sensory 891 HCEOF01 Neural/Sensory,Reproductive 892 HCEOF01 Neural/Sensory, Reproductive 893 HCEON94Immune/Hematopoietic, Neural/Sensory, Reproductive 894 HCEOQ67 Cancer895 HCEOV48 Cancer 896 HCEPC90 Neural/Sensory 897 HCEPO08 Cancer 898HCESB03 Immune/Hematopoietic, Neural/Sensory 899 HCESK44 Cancer 900HCETE08 Mixed Fetal, Neural/Sensory, Reproductive 901 HCETL19Immune/Hematopoietic, Neural/Sensory, Reproductive 902 HCEWD90 Cancer903 HCEWE62 Neural/Sensory 904 HCEZW14 Cancer 905 HCFAT42Immune/Hematopoietic 906 HCFAT66 Immune/Hematopoietic 907 HCFBA30Cardiovascular, Immune/Hematopoietic, Reproductive 908 HCFBM77Immune/Hematopoietic 909 HCFBV39 Cancer 910 HCFCB72 Immune/Hematopoietic911 HCFCG91 Cancer 912 HCFCM81 Digestive, Immune/Hematopoietic,Reproductive 913 HCFCW39 Cancer 914 HCFCY49 Cancer 915 HCFDD18Digestive, Immune/Hematopoietic, Mixed Fetal 916 HCFLB10 Cardiovascular,Immune/Hematopoietic 917 HCFLC03 Cancer 918 HCFLJ52 Cancer 919 HCFLL33Immune/Hematopoietic, Reproductive 920 HCFLP48 Immune/Hematopoietic 921HCFLQ12 Cancer 922 HCFLY20 Cancer 923 HCFLY20 Cancer 924 HCFMA39Immune/Hematopoietic 925 HCFMJ40 Immune/Hematopoietic 926 HCFML07 Cancer927 HCFMR75 Digestive, Immune/Hematopoietic 928 HCFMX16Immune/Hematopoietic 929 HCFMX88 Immune/Hematopoietic, Neural/Sensory930 HCFNM40 Digestive, Immune/Hematopoietic, Reproductive 931 HCFNM50Immune/Hematopoietic 932 HCFNN16 Cancer 933 HCFNN75 Cancer 934 HCFOG17Immune/Hematopoietic 935 HCFOH93 Immune/Hematopoietic, Reproductive 936HCGBA15 Cancer 937 HCHAC68 Cancer 938 HCHBP49 Cancer 939 HCHCA79Digestive, Neural/Sensory, Reproductive 940 HCHCG33 Cancer 941 HCHMY57Cancer 942 HCHOC06 Reproductive 943 HCHOY52 Cancer 944 HCHQB93 Cancer945 HCHQB93 Cancer 946 HCLBK61 Cancer 947 HCLCU75 Respiratory 948HCMSA37 Cardiovascular 949 HCMSR07 Cardiovascular 950 HCNAI74 Digestive951 HCNCT01 Digestive 952 HCNDR39 Cancer 953 HCNSD91 Cancer 954 HCNSF01Cancer 955 HCNSG06 Digestive, Reproductive 956 HCNSG32 Digestive,Reproductive 957 HCPAE41 Cancer 958 HCQAK36 Cancer 959 HCQAQ47 Cancer960 HCQAS72 Cancer 961 HCQBM95 Digestive, Immune/Hematopoietic 962HCQCM95 Cancer 963 HCQCM95 Cancer 964 HCQCV23 Cancer 965 HCQCV23 Cancer966 HCQDD32 Digestive, Immune/Hematopoietic, Reproductive 967 HCQDD61Digestive, Immune/Hematopoietic 968 HCQDT67 Digestive,Immune/Hematopoietic 969 HCRAI29 Neural/Sensory 970 HCRBI79 Cancer 971HCRBL20 Cancer 972 HCRBX84 Cancer 973 HCRMA24 Digestive, Musculoskeletal974 HCRMR35 Cancer 975 HCRMR35 Cancer 976 HCRMR35 Cancer 977 HCROC18Cancer 978 HCUAE53 Immune/Hematopoietic 979 HCUAO46 Immune/Hematopoietic980 HCUAT74 Cancer 981 HCUBA28 Cancer 982 HCUBC45 Cancer 983 HCUBM41Immune/Hematopoietic 984 HCUBN69 Immune/Hematopoietic 985 HCUBY47Digestive, Immune/Hematopoietic 986 HCUCV66 Cancer 987 HCUDJ41Immune/Hematopoietic 988 HCUEC55 Immune/Hematopoietic 989 HCUEG85Immune/Hematopoietic 990 HCUES35 Immune/Hematopoietic, Neural/Sensory991 HCUFC77 Cancer 992 HCUFD17 Cancer 993 HCUFD46 Immune/Hematopoietic994 HCUFE33 Immune/Hematopoietic 995 HCUFJ09 Cancer 996 HCUFQ58Cardiovascular, Immune/Hematopoietic 997 HCUFQ58 Cardiovascular,Immune/Hematopoietic 998 HCUFX08 Immune/Hematopoietic 999 HCUGB76Immune/Hematopoietic, Reproductive 1000 HCUGK79 Immune/Hematopoietic1001 HCUGQ19 Immune/Hematopoietic 1002 HCUGR26 Immune/Hematopoietic 1003HCUGR86 Immune/Hematopoietic 1004 HCUHE27 Immune/Hematopoietic 1005HCUHL82 Cardiovascular, Immune/Hematopoietic, Reproductive 1006 HCUHM71Immune/Hematopoietic, Musculoskeletal 1007 HCWAK88 Immune/Hematopoietic1008 HCWAL10 Cardiovascular, Immune/Hematopoietic 1009 HCWAT71Immune/Hematopoietic 1010 HCWBQ52 Immune/Hematopoietic 1011 HCWCH16Immune/Hematopoietic 1012 HCWDM69 Digestive, Immune/Hematopoietic 1013HCWEB38 Immune/Hematopoietic 1014 HCWEB72 Immune/Hematopoietic 1015HCWEF04 Cancer 1016 HCWEI82 Immune/Hematopoietic 1017 HCWEM96 Cancer1018 HCWFJ16 Immune/Hematopoietic 1019 HCWFJ16 Immune/Hematopoietic 1020HCWFK03 Cancer 1021 HCWHD30 Immune/Hematopoietic 1022 HCWHT34Immune/Hematopoietic, Mixed Fetal 1023 HCWHT52 Immune/Hematopoietic 1024HCWKO32 Immune/Hematopoietic 1025 HCWLE50 Immune/Hematopoietic 1026HCWUF93 Cancer 1027 HCWUW24 Immune/Hematopoietic 1028 HCYBA32 Cancer1029 HDAAV67 Musculoskeletal, Neural/Sensory 1030 HDABR74 Cancer 1031HDABW45 Immune/Hematopoietic, Musculoskeletal 1032 HDACJ52 Cancer 1033HDCBM09 Immune/Hematopoietic 1034 HDFAB86 Mixed Fetal, Neural/Sensory1035 HDFIB37 Connective/Epithelial, Neural/Sensory 1036 HDFMB91Neural/Sensory 1037 HDHAA55 Immune/Hematopoietic, Neural/Sensory 1038HDHEA33 Cancer 1039 HDHEB12 Immune/Hematopoietic, Neural/Sensory 1040HDHEB80 Neural/Sensory 1041 HDHIA16 Cancer 1042 HDHIA26 Neural/Sensory1043 HDHMA71 Cancer 1044 HDLAL94 Cancer 1045 HDPAB86 Cancer 1046 HDPAE80Cancer 1047 HDPAQ86 Digestive, Immune/Hematopoietic, Neural/Sensory 1048HDPBD56 Cancer 1049 HDPBN48 Digestive, Immune/Hematopoietic 1050 HDPCG79Digestive, Immune/Hematopoietic, Reproductive 1051 HDPCV29Immune/Hematopoietic 1052 HDPDA36 Immune/Hematopoietic 1053 HDPDC59Immune/Hematopoietic, Musculoskeletal 1054 HDPFG13 Cancer 1055 HDPFK27Immune/Hematopoietic, Neural/Sensory 1056 HDPFZ05 Immune/Hematopoietic,Neural/Sensory 1057 HDPGA84 Cancer 1058 HDPGR80 Cancer 1059 HDPGU14Cancer 1060 HDPGX09 Cancer 1061 HDPIE44 Cancer 1062 HDPIE73Immune/Hematopoietic 1063 HDPIF35 Immune/Hematopoietic 1064 HDPIF65Immune/Hematopoietic 1065 HDPIH25 Cancer 1066 HDPIY31 Cancer 1067HDPJH72 Cancer 1068 HDPJV53 Immune/Hematopoietic 1069 HDPJV75 Cancer1070 HDPKC55 Cardiovascular, Immune/Hematopoietic, Reproductive 1071HDPKD16 Cancer 1072 HDPMC52 Digestive, Immune/Hematopoietic,Musculoskeletal 1073 HDPML04 Connective/Epithelial, Immune/Hematopoietic1074 HDPMM22 Immune/Hematopoietic 1075 HDPNC21 Cancer 1076 HDPNJ26Cancer 1077 HDPOD73 Immune/Hematopoietic 1078 HDPOT33 Cancer 1079HDPPB70 Cancer 1080 HDPPC19 Immune/Hematopoietic 1081 HDPPE05 Cancer1082 HDPSA70 Cancer 1083 HDPSS56 Cancer 1084 HDPSZ07Immune/Hematopoietic 1085 HDPSZ07 Immune/Hematopoietic 1086 HDPSZ07Immune/Hematopoietic 1087 HDPTI49 Immune/Hematopoietic, Neural/Sensory1088 HDPTP22 Immune/Hematopoietic, Neural/Sensory, Reproductive 1089HDPYE25 Immune/Hematopoietic, Neural/Sensory 1090 HDQGD06 Cancer 1091HDQGD06 Cancer 1092 HDQGD06 Cancer 1093 HDQGN08 Immune/Hematopoietic1094 HDQGO62 Cancer 1095 HDQPM16 Cancer 1096 HDRAA17 Cancer 1097 HDRAC68Cancer 1098 HDSAC78 Cancer 1099 HDSAH37 Connective/Epithelial 1100HDSAM57 Immune/Hematopoietic 1101 HDSAO14 Cancer 1102 HDSAO64 Cancer1103 HDSAP15 Cancer 1104 HDTAR39 Cancer 1105 HDTAS57 Cancer 1106 HDTBP62Cancer 1107 HDTBQ77 Cancer 1108 HDTDA48 Immune/Hematopoietic,Neural/Sensory 1109 HDTDE66 Cancer 1110 HDTDG75 Immune/Hematopoietic1111 HDTDS09 Cancer 1112 HDTFF53 Cancer 1113 HDTGW76 Cancer 1114 HDTGZ56Immune/Hematopoietic 1115 HDTHZ85 Cancer 1116 HDTIM39 Cancer 1117HDTKJ29 Cancer 1118 HDUAB12 Cancer 1119 HDUAD68 Cancer 1120 HE2AC74Cancer 1121 HE2AC74 Cancer 1122 HE2AC75 Mixed Fetal 1123 HE2AI94 Cancer1124 HE2AT61 Cancer 1125 HE2AX36 Cancer 1126 HE2AY96 Cancer 1127 HE2BD72Cancer 1128 HE2BH50 Cancer 1129 HE2CB53 Cancer 1130 HE2CC17 Excretory,Mixed Fetal 1131 HE2CJ53 Cancer 1132 HE2CK47 Cancer 1133 HE2CM34 Cancer1134 HE2DG46 Mixed Fetal 1135 HE2DI16 Mixed Fetal 1136 HE2DJ84 Cancer1137 HE2DY23 Cancer 1138 HE2DY25 Cancer 1139 HE2EE80 Cancer 1140 HE2EH45Mixed Fetal 1141 HE2FE89 Cardiovascular, Digestive, Mixed Fetal 1142HE2FR49 Cancer 1143 HE2GB19 Cancer 1144 HE2GO81 Cancer 1145 HE2HB61Mixed Fetal 1146 HE2HB64 Cancer 1147 HE2HF76 Cancer 1148 HE2ID09 MixedFetal 1149 HE2IE66 Cancer 1150 HE2NW57 Mixed Fetal 1151 HE2OA95 Cancer1152 HE2OC39 Mixed Fetal, Musculoskeletal 1153 HE2PB61 Cancer 1154HE2PI43 Cancer 1155 HE2PJ56 Cancer 1156 HE6CJ41 Immune/Hematopoietic,Mixed Fetal 1157 HE6DC37 Digestive, Mixed Fetal, Reproductive 1158HE6DN83 Cancer 1159 HE6EI30 Immune/Hematopoietic, Mixed Fetal 1160HE6ET70 Mixed Fetal, Reproductive 1161 HE6GO65 Mixed Fetal,Neural/Sensory 1162 HE8AN83 Mixed Fetal, Musculoskeletal 1163 HE8AU68Cancer 1164 HE8BE20 Cancer 1165 HE8BP05 Mixed Fetal 1166 HE8BP64 Cancer1167 HE8BQ49 Mixed Fetal 1168 HE8BR18 Cancer 1169 HE8BR30 Mixed Fetal1170 HE8BT58 Cancer 1171 HE8BU60 Cancer 1172 HE8CA13 Cancer 1173 HE8CC34Cardiovascular, Digestive, Mixed Fetal 1174 HE8CH08 Cancer 1175 HE8DG02Mixed Fetal 1176 HE8DK52 Cancer 1177 HE8DZ94 Cancer 1178 HE8EN79 Cancer1179 HE8EX86 Cancer 1180 HE8FC10 Immune/Hematopoietic, Mixed Fetal,Reproductive 1181 HE8FG15 Cancer 1182 HE8FG24 Cancer 1183 HE8FK78 Cancer1184 HE8FL24 Mixed Fetal 1185 HE8FL68 Mixed Fetal 1186 HE8FR53 Cancer1187 HE8MA27 Cancer 1188 HE8MG56 Mixed Fetal 1189 HE8MQ01 Cancer 1190HE8MS43 Cancer 1191 HE8MY77 Cancer 1192 HE8NC81 Cancer 1193 HE8NO09Cancer 1194 HE8QU21 Immune/Hematopoietic, Mixed Fetal 1195 HE8SH74Immune/Hematopoietic, Mixed Fetal, Musculoskeletal 1196 HE8UX34 MixedFetal 1197 HE9AE05 Cancer 1198 HE9BJ14 Mixed Fetal, Musculoskeletal 1199HE9CI81 Cancer 1200 HE9CJ38 Mixed Fetal 1201 HE9CM11 Mixed Fetal 1202HE9CN58 Cancer 1203 HE9CV59 Cancer 1204 HE9DG54 Cancer 1205 HE9DH59Cancer 1206 HE9DZ47 Endocrine, Immune/Hematopoietic, Mixed Fetal 1207HE9EC36 Cancer 1208 HE9EM54 Immune/Hematopoietic, Mixed Fetal 1209HE9FH28 Mixed Fetal 1210 HE9HE13 Cancer 1211 HE9HE13 Cancer 1212 HE9HF59Mixed Fetal 1213 HE9HV71 Cancer 1214 HE9NB82 Cancer 1215 HE9NE43 MixedFetal 1216 HE9RN58 Cancer 1217 HE9TA42 Cancer 1218 HEAAC21 Cancer 1219HEAAC39 Neural/Sensory, Reproductive 1220 HEAAC48 Reproductive 1221HEAAD63 Neural/Sensory, Reproductive 1222 HEAAE19 Immune/Hematopoietic,Reproductive 1223 HEAAM54 Reproductive 1224 HEAAM96 Reproductive 1225HEAAN52 Cancer 1226 HEAAU28 Reproductive 1227 HEAAW54 Reproductive 1228HEAAW94 Cancer 1229 HEBAP51 Cancer 1230 HEBAT05 Cancer 1231 HEBBF78Cancer 1232 HEBBK04 Cancer 1233 HEBCN80 Neural/Sensory 1234 HEBCW57Mixed Fetal, Neural/Sensory 1235 HEBDF90 Cancer 1236 HEBDW31 Cancer 1237HEBFL36 Neural/Sensory 1238 HEBGC01 Neural/Sensory 1239 HEBGE23 Cancer1240 HEBGE85 Digestive, Neural/Sensory, Reproductive 1241 HEBGJ94 Cancer1242 HEBGM06 Cancer 1243 HEEAB58 Cancer 1244 HEEAF49 Cancer 1245 HEEAJ46Mixed Fetal, Reproductive 1246 HEGAI20 Reproductive 1247 HEIAC52 Cancer1248 HELAC55 Cardiovascular, Immune/Hematopoietic, Musculoskeletal 1249HELAT58 Cardiovascular 1250 HELAW94 Cancer 1251 HELDF80 Cancer 1252HELDH39 Cancer 1253 HELDK79 Cardiovascular 1254 HELDQ42 Cancer 1255HELEE85 Cancer 1256 HELEL76 Cancer 1257 HELEL76 Cancer 1258 HELEO45Cancer 1259 HELFA57 Cancer 1260 HELFO30 Cancer 1261 HELGF28 Cancer 1262HELGP60 Cardiovascular, Excretory, Immune/Hematopoietic 1263 HELHN47Cancer 1264 HELHP11 Cardiovascular, Immune/Hematopoietic 1265 HELHP11Cardiovascular, Immune/Hematopoietic 1266 HEMAE30 Cancer 1267 HEMBV40Cancer 1268 HEMCJ80 Cancer 1269 HEMCL55 Cardiovascular 1270 HEMDB07Cardiovascular 1271 HEMDR05 Cardiovascular, Digestive,Immune/Hematopoietic 1272 HEMGK71 Cardiovascular, Immune/Hematopoietic,Musculoskeletal 1273 HEOMF59 Immune/Hematopoietic 1274 HEOMJ73 Cancer1275 HEOMR67 Cancer 1276 HEOMU25 Connective/Epithelial,Immune/Hematopoietic 1277 HEOMU44 Cancer 1278 HEONI85 Digestive,Immune/Hematopoietic, Reproductive 1279 HEONK04 Cancer 1280 HEONP08Immune/Hematopoietic 1281 HEPAD15 Endocrine, Reproductive 1282 HEPBC23Cancer 1283 HEPBV09 Reproductive 1284 HEPCF35 Neural/Sensory,Reproductive 1285 HEPCU48 Cancer 1286 HEQAH47 Cancer 1287 HEQAP92 Cancer1288 HEQAV53 Cancer 1289 HEQBJ01 Cancer 1290 HEQBJ01 Cancer 1291 HEQBJ01Cancer 1292 HEQBM94 Cancer 1293 HEQCB93 Cancer 1294 HERAI63Connective/Epithelial 1295 HERAQ22 Connective/Epithelial 1296 HERAS61Connective/Epithelial 1297 HESAG57 Cancer 1298 HETAA62 Cancer 1299HETBB70 Immune/Hematopoietic, Reproductive 1300 HETBJ88 Cancer 1301HETCM67 Cancer 1302 HETDD61 Reproductive 1303 HETDD61 Reproductive 1304HETDJ34 Cancer 1305 HETDM73 Cancer 1306 HETDP76 Cancer 1307 HETFO57Cancer 1308 HETGZ31 Cancer 1309 HETHD26 Cancer 1310 HETHM27 Cancer 1311HETIN36 Cancer 1312 HFAAI17 Neural/Sensory 1313 HFAAJ45Immune/Hematopoietic, Neural/Sensory 1314 HFADF41 Neural/Sensory 1315HFADM09 Cancer 1316 HFAUA23 Cancer 1317 HFCAG75 Cancer 1318 HFCAI40Cancer 1319 HFCAQ17 Cancer 1320 HFCBC16 Neural/Sensory 1321 HFCBL53Cancer 1322 HFCBL53 Cancer 1323 HFCBL53 Cancer 1324 HFCBT29 Cancer 1325HFCCZ31 Cancer 1326 HFCDN13 Cancer 1327 HFCDT67 Cancer 1328 HFCDY36Neural/Sensory 1329 HFCEC45 Cancer 1330 HFCET43 Cancer 1331 HFEAG55Cancer 1332 HFEAU63 Connective/Epithelial 1333 HFEBA88 Cancer 1334HFEBK75 Connective/Epithelial 1335 HFEBO15 Cancer 1336 HFEBO17 Cancer1337 HFFAE46 Neural/Sensory 1338 HFFAH01 Digestive,Immune/Hematopoietic, Neural/Sensory 1339 HFFAL70 Cancer 1340 HFFAV61Neural/Sensory 1341 HFGAB50 Cancer 1342 HFGAE28 Cancer 1343 HFGAN63Cancer 1344 HFHDN80 Cardiovascular, Digestive, Immune/Hematopoietic 1345HFIAB78 Cancer 1346 HFIAD23 Cancer 1347 HFIAK06 Musculoskeletal,Reproductive 1348 HFICH70 Musculoskeletal 1349 HFIHQ57 Musculoskeletal,Reproductive 1350 HFIIK29 Cancer 1351 HFIIK29 Cancer 1352 HFIIK29 Cancer1353 HFIIK29 Cancer 1354 HFIIQ27 Cancer 1355 HFIIQ64 Cancer 1356 HFIIZ61Cancer 1357 HFIJD81 Cancer 1358 HFIJF44 Cancer 1359 HFITA02Immune/Hematopoietic, Musculoskeletal 1360 HFITF80 Cancer 1361 HFIUK66Cancer 1362 HFIUT21 Cancer 1363 HFIVB04 Cancer 1364 HFIXC39 Cancer 1365HFIXC69 Cancer 1366 HFIXE39 Cancer 1367 HFIYP15 Immune/Hematopoietic,Musculoskeletal 1368 HFIZE10 Cancer 1369 HFIZF51 Musculoskeletal 1370HFIZK42 Immune/Hematopoietic, Musculoskeletal 1371 HFIZM89Musculoskeletal 1372 HFKBA62 Digestive, Excretory, Neural/Sensory 1373HFKBC47 Cancer 1374 HFKDX53 Cancer 1375 HFKEB14 Cancer 1376 HFKEG63Excretory 1377 HFKES35 Cancer 1378 HFKES35 Cancer 1379 HFKEU17 Cancer1380 HFKEV77 Cancer 1381 HFKFI15 Cancer 1382 HFKFI35 Excretory 1383HFKFK49 Cancer 1384 HFKFV88 Cancer 1385 HFKFV88 Cancer 1386 HFKFV88Cancer 1387 HFKFX64 Excretory 1388 HFOXD49 Cancer 1389 HFOXE28 Cancer1390 HFOYH74 Musculoskeletal 1391 HFOYP02 Musculoskeletal 1392 HFOYR24Musculoskeletal 1393 HFOYR54 Cancer 1394 HFOZB26 Cancer 1395 HFPBF54Cancer 1396 HFPBF54 Cancer 1397 HFPBI93 Cancer 1398 HFPBJ64Musculoskeletal, Neural/Sensory 1399 HFPBQ55 Musculoskeletal,Neural/Sensory, Reproductive 1400 HFPCK22 Cancer 1401 HFPCM32Neural/Sensory 1402 HFPCM36 Cancer 1403 HFPCS84 Neural/Sensory 1404HFPCU47 Neural/Sensory 1405 HFPCY66 Digestive, Neural/Sensory 1406HFPDC65 Cancer 1407 HFPDE42 Musculoskeletal, Neural/Sensory 1408 HFPDE88Neural/Sensory 1409 HFPDO25 Neural/Sensory 1410 HFPDP70 Neural/Sensory1411 HFPDR39 Cancer 1412 HFPDX08 Cancer 1413 HFPEP69 Neural/Sensory 1414HFRAU40 Cancer 1415 HFRAY90 Cancer 1416 HFSAY91 Cancer 1417 HFSBC10Immune/Hematopoietic, Mixed Fetal 1418 HFSBE94 Immune/Hematopoietic 1419HFTAN11 Cancer 1420 HFTAR27 Cancer 1421 HFTAR30 Cancer 1422 HFTAS49Cancer 1423 HFTBB50 Cancer 1424 HFTBL17 Cancer 1425 HFTBL17 Cancer 1426HFTCF02 Digestive, Musculoskeletal, Neural/Sensory 1427 HFTCI85Neural/Sensory 1428 HFTCJ32 Neural/Sensory 1429 HFTCO17 Cancer 1430HFTCW07 Neural/Sensory 1431 HFTDF32 Cancer 1432 HFTDF79Immune/Hematopoietic, Neural/Sensory, Reproductive 1433 HFTDK11 Cancer1434 HFTDU08 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory 1435HFVGK67 Digestive, Immune/Hematopoietic 1436 HFVHD38 Cancer 1437 HFVHY57Cancer 1438 HFVIC33 Cancer 1439 HFXAK32 Cancer 1440 HFXAK59 Cancer 1441HFXBI64 Neural/Sensory 1442 HFXBL05 Mixed Fetal, Neural/Sensory 1443HFXBM52 Neural/Sensory 1444 HFXBR58 Neural/Sensory 1445 HFXBV67Digestive, Neural/Sensory 1446 HFXBY20 Neural/Sensory 1447 HFXCB70Neural/Sensory 1448 HFXCI42 Neural/Sensory 1449 HFXCL59Immune/Hematopoietic, Musculoskeletal, Neural/Sensory 1450 HFXCM22Neural/Sensory, Reproductive 1451 HFXCN18 Neural/Sensory 1452 HFXCS53Cancer 1453 HFXDB37 Neural/Sensory 1454 HFXDI32 Neural/Sensory 1455HFXDJ43 Neural/Sensory 1456 HFXDL76 Immune/Hematopoietic,Musculoskeletal, Neural/Sensory 1457 HFXDM75 Neural/Sensory 1458 HFXDO18Neural/Sensory 1459 HFXDP44 Neural/Sensory 1460 HFXDR08Immune/Hematopoietic, Neural/Sensory, Reproductive 1461 HFXDR28Neural/Sensory 1462 HFXDR28 Neural/Sensory 1463 HFXDR47 Cancer 1464HFXDZ03 Immune/Hematopoietic, Neural/Sensory 1465 HFXED33 Neural/Sensory1466 HFXEE88 Neural/Sensory 1467 HFXGR32 Neural/Sensory 1468 HFXGT51Neural/Sensory 1469 HFXGW16 Neural/Sensory 1470 HFXHC15 Neural/Sensory1471 HFXHI33 Immune/Hematopoietic, Neural/Sensory 1472 HFXHL21Neural/Sensory 1473 HFXHL83 Neural/Sensory 1474 HFXHM49 Neural/Sensory1475 HFXHM93 Neural/Sensory 1476 HFXHN89 Immune/Hematopoietic,Neural/Sensory 1477 HFXJB21 Neural/Sensory 1478 HFXJN93 Neural/Sensory1479 HFXJS15 Cancer 1480 HFXJT53 Cancer 1481 HFXKG56 Neural/Sensory 1482HFXKL60 Cancer 1483 HFXLG08 Neural/Sensory 1484 HFXLK91 Cancer 1485HFXLM32 Neural/Sensory, Reproductive 1486 HGBAX83 Digestive 1487 HGBBR29Cancer 1488 HGBDL51 Cancer 1489 HGBDV35 Cancer 1490 HGBDX28 Cancer 1491HGBGX31 Cancer 1492 HGBHE23 Cancer 1493 HGBHI15 Digestive 1494 HGCMW39Cancer 1495 HGLAG32 Cancer 1496 HGLAH08 Cancer 1497 HGLAH86Immune/Hematopoietic 1498 HGLBC33 Cancer 1499 HGLBG15 Cancer 1500HGLBM55 Cancer 1501 HGLDA95 Cancer 1502 HGLDB06 Cancer 1503 HGLDE15Digestive, Immune/Hematopoietic 1504 HHBEI14 Cancer 1505 HHBGL33Cardiovascular, Digestive 1506 HHEAW44 Immune/Hematopoietic 1507 HHEBP28Cancer 1508 HHECK41 Cancer 1509 HHECR10 Immune/Hematopoietic 1510HHEMC55 Immune/Hematopoietic 1511 HHEMM20 Immune/Hematopoietic 1512HHEMM80 Immune/Hematopoietic 1513 HHEMP35 Cancer 1514 HHEMZ08 Cancer1515 HHENC17 Cancer 1516 HHENF95 Immune/Hematopoietic 1517 HHENR74Immune/Hematopoietic 1518 HHENU33 Immune/Hematopoietic 1519 HHENY07Cancer 1520 HHEOK77 Cancer 1521 HHEPE72 Immune/Hematopoietic 1522HHEPE81 Cancer 1523 HHEPM64 Cancer 1524 HHEQI04 Connective/Epithelial,Excretory, Immune/Hematopoietic 1525 HHEQY60 Immune/Hematopoietic 1526HHFBA31 Cancer 1527 HHFCI81 Cancer 1528 HHFCN78 Cardiovascular,Immune/Hematopoietic 1529 HHFCT95 Cancer 1530 HHFDN16 Cardiovascular1531 HHFEB79 Connective/Epithelial 1532 HHFEC39 Cancer 1533 HHFEN34Cardiovascular 1534 HHFFZ01 Cancer 1535 HHFGI71 Cardiovascular 1536HHFGJ54 Cancer 1537 HHFGL38 Cardiovascular, Immune/Hematopoietic 1538HHFGR75 Cardiovascular, Immune/Hematopoietic, Neural/Sensory 1539HHFGZ23 Cardiovascular, Digestive, Endocrine 1540 HHFHG26Cardiovascular, Neural/Sensory 1541 HHFHM47 Cardiovascular,Immune/Hematopoietic 1542 HHGAA76 Immune/Hematopoietic, Reproductive1543 HHGAD46 Cancer 1544 HHGAT09 Cancer 1545 HHGBC21 Cancer 1546 HHGBF91Cancer 1547 HHGBG63 Cancer 1548 HHGBV02 Immune/Hematopoietic,Reproductive 1549 HHGBW55 Immune/Hematopoietic, Reproductive 1550HHGBX88 Cancer 1551 HHGCA26 Reproductive 1552 HHGDA81 Cancer 1553HHGDI12 Neural/Sensory 1554 HHGDR05 Neural/Sensory 1555 HHGDR92 Cancer1556 HHGDS56 Cancer 1557 HHGDW65 Cancer 1558 HHLBA86 Digestive 1559HHNAC56 Digestive 1560 HHPBG90 Cancer 1561 HHPDE28 Cancer 1562 HHPDJ11Cancer 1563 HHPDX86 Neural/Sensory 1564 HHPEA17 Neural/Sensory 1565HHPEB61 Immune/Hematopoietic, Neural/Sensory, Respiratory 1566 HHPFP26Cancer 1567 HHPFS11 Cardiovascular, Neural/Sensory 1568 HHPFS15 Cancer1569 HHPFS18 Cancer 1570 HHPGH34 Neural/Sensory, Reproductive 1571HHPGU74 Neural/Sensory 1572 HHPGU87 Cancer 1573 HHPSD42Immune/Hematopoietic, Neural/Sensory 1574 HHPSE03 Neural/Sensory 1575HHPSE55 Cancer 1576 HHPSF70 Cancer 1577 HHPSH74 Cancer 1578 HHPSL14Cancer 1579 HHPSM40 Neural/Sensory 1580 HHPTF26 Mixed Fetal,Musculoskeletal, Neural/Sensory 1581 HHSAD31 Immune/Hematopoietic,Neural/Sensory, Reproductive 1582 HHSAE74 Neural/Sensory 1583 HHSAG62Cancer 1584 HHSAK17 Neural/Sensory 1585 HHSBJ92 Cancer 1586 HHSBN84Cancer 1587 HHSCL24 Cancer 1588 HHSCQ67 Cancer 1589 HHSCU12 Cancer 1590HHSDB43 Cancer 1591 HHSDL07 Neural/Sensory 1592 HHSDX07 Cancer 1593HHSFF54 Cancer 1594 HHSGB85 Cancer 1595 HHSGL84 Neural/Sensory 1596HHTLH79 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory 1597HIABC70 Cancer 1598 HIATG10 Endocrine 1599 HIBCO70 Cancer 1600 HIBCR82Mixed Fetal, Neural/Sensory 1601 HIBDA41 Cancer 1602 HIBEC45 Cancer 1603HILBW03 Cancer 1604 HISAE16 Digestive 1605 HISAG53 Cancer 1606 HISAN63Digestive 1607 HISAT78 Cancer 1608 HISBA38 Digestive,Immune/Hematopoietic 1609 HISBB66 Cancer 1610 HISCJ20 Cancer 1611HISCK41 Digestive 1612 HISCO45 Cancer 1613 HISEJ52 Cancer 1614 HJABC58Cancer 1615 HJABG59 Immune/Hematopoietic 1616 HJABR75Immune/Hematopoietic 1617 HJABS31 Cancer 1618 HJABT12 Digestive,Immune/Hematopoietic, Neural/Sensory 1619 HJACE25 Cancer 1620 HJACK21Cancer 1621 HJBCG74 Cancer 1622 HJBCO21 Cancer 1623 HJBCQ40Immune/Hematopoietic 1624 HJBDM36 Cancer 1625 HJMAF30 Cancer 1626HJMAM72 Cancer 1627 HJMAZ60 Cancer 1628 HJMBB20 Cancer 1629 HJMBB20Cancer 1630 HJMBB20 Cancer 1631 HJMBK59 Cancer 1632 HJMBP01 Cancer 1633HJMBQ17 Cancer 1634 HJMBW62 Reproductive 1635 HJMBX54 Musculoskeletal,Reproductive 1636 HJPAF69 Immune/Hematopoietic 1637 HJPAQ19 Cancer 1638HJPAZ35 Cancer 1639 HJPBI77 Immune/Hematopoietic, Musculoskeletal,Neural/Sensory 1640 HJPBN96 Cancer 1641 HJPBU47 Cancer 1642 HJPCQ19Cancer 1643 HJPDJ08 Immune/Hematopoietic 1644 HJPDK61 Cancer 1645HKABI53 Cancer 1646 HKABN63 Cancer 1647 HKACA25 Cancer 1648 HKACO64Cancer 1649 HKACP50 Cancer 1650 HKACX90 Cancer 1651 HKADI27 Cancer 1652HKADN26 Cancer 1653 HKADP79 Cancer 1654 HKADT55 Cancer 1655 HKAEK58Cancer 1656 HKAEK72 Connective/Epithelial 1657 HKAFJ47 Cancer 1658HKAFQ41 Cancer 1659 HKAHH71 Cancer 1660 HKAJA95 Cancer 1661 HKAKU90Cancer 1662 HKCSZ54 Digestive 1663 HKFAA15 Cancer 1664 HKFBB08Immune/Hematopoietic 1665 HKGAG59 Cancer 1666 HKGAJ81 Cancer 1667HKGAK45 Musculoskeletal, Reproductive 1668 HKGAP04 Cancer 1669 HKGAP57Immune/Hematopoietic 1670 HKGAW41 Cancer 1671 HKGBA21Connective/Epithelial, Mixed Fetal, Musculoskeletal 1672 HKGBC33Immune/Hematopoietic 1673 HKGBC73 Cancer 1674 HKGBF61 Cancer 1675HKGBH54 Cancer 1676 HKGBP52 Cancer 1677 HKGCE23 Cancer 1678 HKGCE62Immune/Hematopoietic 1679 HKGCK41 Cancer 1680 HKGCK41 Cancer 1681HKGCN96 Cancer 1682 HKGCX05 Cancer 1683 HKGDA95 Cancer 1684 HKGDO12Cancer 1685 HKIME53 Cancer 1686 HKIMG23 Cancer 1687 HKIXB73 Excretory1688 HKIXD68 Cancer 1689 HKIXR91 Cancer 1690 HKIXS19 Cancer 1691 HKIXW45Cancer 1692 HKIYU90 Excretory, Neural/Sensory 1693 HKIMLB81 Excretory1694 HKMLF77 Excretory 1695 HKMLM32 Excretory, Neural/Sensory 1696HKMLR17 Cancer 1697 HKMLT89 Excretory, Immune/Hematopoietic,Reproductive 1698 HKMLV05 Excretory, Immune/Hematopoietic 1699 HKMLV25Cancer 1700 HKMMB79 Cancer 1701 HKMMC69 Excretory, Immune/Hematopoietic1702 HKMMD91 Cancer 1703 HKMMP90 Excretory, Immune/Hematopoietic,Neural/Sensory 1704 HKMMU76 Cancer 1705 HKPAC10 Excretory 1706 HKPAC50Cancer 1707 HKPMA08 Cancer 1708 HKTAC18 Cancer 1709 HL1SA89 Cancer 1710HL2AB60 Cancer 1711 HL3AE69 Cancer 1712 HL3AF32 Cancer 1713 HLDAV70Digestive, Immune/Hematopoietic 1714 HLDBL62 Cancer 1715 HLDBV18 Cancer1716 HLDBV54 Cancer 1717 HLDCR26 Cancer 1718 HLDDM27 Cancer 1719 HLDDM27Cancer 1720 HLDNF18 Cancer 1721 HLDNN84 Digestive, Mixed Fetal 1722HLDOD77 Digestive 1723 HLDOL74 Cancer 1724 HLDPB24 Cardiovascular,Digestive 1725 HLDRU08 Cancer 1726 HLDXF43 Cancer 1727 HLEAA10Immune/Hematopoietic 1728 HLEAA24 Immune/Hematopoietic 1729 HLHAE14Neural/Sensory, Respiratory 1730 HLHAE14 Neural/Sensory, Respiratory1731 HLHBS54 Cancer 1732 HLHCB33 Digestive, Reproductive, Respiratory1733 HLHCF14 Connective/Epithelial, Respiratory 1734 HLHCG24 Cancer 1735HLHCH20 Cancer 1736 HLHCN51 Digestive, Immune/Hematopoietic, Respiratory1737 HLHCT96 Cancer 1738 HLHDC33 Immune/Hematopoietic, Reproductive,Respiratory 1739 HLHDF92 Cancer 1740 HLHDJ05 Respiratory 1741 HLHDL37Respiratory 1742 HLHDL69 Cancer 1743 HLHDL69 Cancer 1744 HLHDL69 Cancer1745 HLHDL69 Cancer 1746 HLHDM38 Cancer 1747 HLHDR92 Neural/Sensory,Respiratory 1748 HLHDY94 Cancer 1749 HLHEE27 Cancer 1750 HLHEE38Connective/Epithelial, Neural/Sensory, Respiratory 1751 HLHEI72Musculoskeletal, Respiratory 1752 HLHEX62 Excretory,Immune/Hematopoietic, Respiratory 1753 HLHFK59 Digestive, Respiratory1754 HLHFP09 Cancer 1755 HLHGG78 Cancer 1756 HLHSG15 Cancer 1757 HLHSQ35Respiratory 1758 HLHTB92 Immune/Hematopoietic, Respiratory 1759 HLHTP55Cancer 1760 HLIBD74 Digestive 1761 HLIBE41 Digestive,Immune/Hematopoietic, Reproductive 1762 HLIBO16 Digestive,Immune/Hematopoietic 1763 HLJBI22 Cancer 1764 HLJEE16 Cancer 1765HLLAX64 Cancer 1766 HLLAX95 Immune/Hematopoietic 1767 HLLCD67Immune/Hematopoietic 1768 HLMBX89 Cancer 1769 HLMBZ14Immune/Hematopoietic 1770 HLMCT51 Immune/Hematopoietic, Reproductive1771 HLMCT95 Cancer 1772 HLMDD65 Cancer 1773 HLMDH01Immune/Hematopoietic 1774 HLMDU23 Immune/Hematopoietic 1775 HLMFB62Immune/Hematopoietic 1776 HLMFG52 Immune/Hematopoietic 1777 HLMFU53Cancer 1778 HLMHG68 Cancer 1779 HLMHN06 Immune/Hematopoietic,Neural/Sensory 1780 HLMHS15 Immune/Hematopoietic 1781 HLMIM84 Cancer1782 HLMIN52 Cancer 1783 HLMIQ83 Immune/Hematopoietic 1784 HLMIW76Immune/Hematopoietic 1785 HLMMA65 Immune/Hematopoietic 1786 HLMMT12Digestive, Immune/Hematopoietic 1787 HLMNA19 Cardiovascular,Immune/Hematopoietic 1788 HLQAD72 Cancer 1789 HLQAM30 Cancer 1790HLQAM59 Digestive 1791 HLQBB23 Cancer 1792 HLQBF05 Digestive,Reproductive 1793 HLQBX64 Cancer 1794 HLQCY09 Digestive 1795 HLQCZ43Cancer 1796 HLQCZ80 Digestive 1797 HLQDK45 Digestive 1798 HLQDM47Digestive 1799 HLQDU77 Cancer 1800 HLSAD72 Connective/Epithelial 1801HLTCJ67 Immune/Hematopoietic 1802 HLTCM28 Immune/Hematopoietic,Respiratory 1803 HLTCO22 Cancer 1804 HLTDA14 Immune/Hematopoietic 1805HLTDC26 Cancer 1806 HLTDC26 Cancer 1807 HLTDI20 Cancer 1808 HLTDI65Immune/Hematopoietic 1809 HLTDK30 Cancer 1810 HLTDL37 Cancer 1811HLTDU35 Cancer 1812 HLTDX04 Cancer 1813 HLTEH84 Cancer 1814 HLTEL39Cardiovascular, Immune/Hematopoietic 1815 HLTEN11 Cancer 1816 HLTEW52Immune/Hematopoietic 1817 HLTEZ36 Cancer 1818 HLTGG14 Cancer 1819HLUAF94 Immune/Hematopoietic 1820 HLWAH33 Mixed Fetal, Reproductive 1821HLWAO11 Cancer 1822 HLWAW73 Cancer 1823 HLWAX50 Cancer 1824 HLWBJ93Cancer 1825 HLWBK16 Cardiovascular, Connective/Epithelial, Reproductive1826 HLWCC11 Reproductive 1827 HLYAH81 Immune/Hematopoietic 1828 HLYAH92Immune/Hematopoietic 1829 HLYAJ79 Cancer 1830 HLYAL28Immune/Hematopoietic 1831 HLYAR30 Cancer 1832 HLYAT54Immune/Hematopoietic 1833 HLYBC81 Connective/Epithelial,Immune/Hematopoietic, Reproductive 1834 HLYBD09 Immune/Hematopoietic1835 HLYBL67 Immune/Hematopoietic 1836 HLYBM38 Digestive,Immune/Hematopoietic 1837 HLYBN23 Immune/Hematopoietic 1838 HLYBN71Immune/Hematopoietic 1839 HLYBS25 Digestive, Immune/Hematopoietic,Reproductive 1840 HLYBT28 Immune/Hematopoietic 1841 HLYBU15Immune/Hematopoietic 1842 HLYBY04 Immune/Hematopoietic 1843 HLYCE15Digestive, Immune/Hematopoietic 1844 HLYCH04 Immune/Hematopoietic 1845HLYCY48 Immune/Hematopoietic 1846 HLYDE38 Immune/Hematopoietic 1847HLYDG55 Immune/Hematopoietic 1848 HLYDO73 Immune/Hematopoietic 1849HLYEA60 Cancer 1850 HLYEJ14 Cancer 1851 HLYEJ44 Cancer 1852 HLYEU51Immune/Hematopoietic 1853 HLYGV19 Cancer 1854 HMABK52Immune/Hematopoietic 1855 HMACF34 Immune/Hematopoietic 1856 HMACL77Cancer 1857 HMACT74 Immune/Hematopoietic 1858 HMADJ14Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal 1859HMADJ74 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal1860 HMAEA58 Cancer 1861 HMAGF01 Cancer 1862 HMAJS26 Cancer 1863 HMCED78Cancer 1864 HMCFN86 Cancer 1865 HMCGJ47 Cancer 1866 HMCGK88 Cancer 1867HMCIH27 Cancer 1868 HMCIQ20 Cardiovascular, Immune/Hematopoietic,Neural/Sensory 1869 HMCJC19 Immune/Hematopoietic 1870 HMDAB44Neural/Sensory 1871 HMDAE88 Neural/Sensory 1872 HMDAG62 Cancer 1873HMDAK20 Neural/Sensory 1874 HMDAM08 Neural/Sensory 1875 HMDAM39Neural/Sensory 1876 HMEAA41 Cancer 1877 HMECM77 Cardiovascular 1878HMEEH21 Cardiovascular 1879 HMEET36 Cancer 1880 HMEEZ07 Cardiovascular,Reproductive 1881 HMEFB15 Cardiovascular 1882 HMEIH57 Cardiovascular,Immune/Hematopoietic 1883 HMEIJ21 Cancer 1884 HMEIX79 Cancer 1885HMEJC96 Cancer 1886 HMEJD36 Cardiovascular, Endocrine,Immune/Hematopoietic 1887 HMEJK28 Cancer 1888 HMEKH55 Cancer 1889HMEKW44 Cardiovascular, Immune/Hematopoietic, Neural/Sensory 1890HMEKW71 Cancer 1891 HMELW26 Cancer 1892 HMGBT32 Cancer 1893 HMHBI09Cancer 1894 HMHBI93 Cancer 1895 HMHBP74 Cancer 1896 HMIAC52 Cancer 1897HMIAD75 Neural/Sensory 1898 HMIAG42 Cancer 1899 HMIAG55 Cancer 1900HMIAG72 Cancer 1901 HMIAL39 Cancer 1902 HMIAO82 Cancer 1903 HMIAR42Cancer 1904 HMLAV33 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory1905 HMIAZ24 Cancer 1906 HMIBD93 Cancer 1907 HMIBE95 Neural/Sensory 1908HMIBG57 Immune/Hematopoietic, Neural/Sensory, Reproductive 1909 HMJAC12Neural/Sensory 1910 HMKAN71 Cancer 1911 HMKBA33 Neural/Sensory 1912HMKCI22 Cancer 1913 HMKCK32 Neural/Sensory 1914 HMKCP81 Cancer 1915HMKCY49 Immune/Hematopoietic, Neural/Sensory 1916 HMKDD51 Neural/Sensory1917 HMKDG69 Cardiovascular, Neural/Sensory 1918 HMKDM80 Neural/Sensory1919 HMKEG88 Neural/Sensory 1920 HMMAA09 Immune/Hematopoietic 1921HMMAK92 Immune/Hematopoietic 1922 HMMAL32 Immune/Hematopoietic 1923HMMBD19 Immune/Hematopoietic, Reproductive 1924 HMMBF22Immune/Hematopoietic, Reproductive 1925 HMMBH91 Immune/Hematopoietic1926 HMMBH94 Immune/Hematopoietic 1927 HMMBK55 Immune/Hematopoietic 1928HMMBQ31 Cardiovascular, Immune/Hematopoietic 1929 HMMBR63 Cancer 1930HMMBS55 Immune/Hematopoietic, Reproductive 1931 HMMBT47Immune/Hematopoietic 1932 HMMCD35 Immune/Hematopoietic 1933 HMMCD95Immune/Hematopoietic, Neural/Sensory 1934 HMPAB26 Cancer 1935 HMPAP48Immune/Hematopoietic 1936 HMQAI38 Immune/Hematopoietic, Reproductive1937 HMQAT69 Cancer 1938 HMQBL90 Digestive, Immune/Hematopoietic 1939HMQBV82 Immune/Hematopoietic, Musculoskeletal, Reproductive 1940 HMQCA75Cancer 1941 HMQCB37 Cancer 1942 HMQCL80 Immune/Hematopoietic 1943HMQCX41 Immune/Hematopoietic 1944 HMQDM09 Cancer 1945 HMQDU07 Digestive,Immune/Hematopoietic, Musculoskeletal 1946 HMSAP33 Immune/Hematopoietic1947 HMSAZ48 Immune/Hematopoietic 1948 HMSBN18 Cancer 1949 HMSBS25Immune/Hematopoietic 1950 HMSBU14 Immune/Hematopoietic 1951 HMSBZ10Immune/Hematopoietic 1952 HMSCB94 Immune/Hematopoietic, Reproductive1953 HMSCK12 Immune/Hematopoietic 1954 HMSCP63 Immune/Hematopoietic 1955HMSCV75 Immune/Hematopoietic 1956 HMSCV85 Immune/Hematopoietic,Reproductive 1957 HMSCW44 Immune/Hematopoietic, Mixed Fetal,Neural/Sensory 1958 HMSCZ19 Cancer 1959 HMSDI67 Digestive,Immune/Hematopoietic 1960 HMSDI79 Cancer 1961 HMSDR28 Cancer 1962HMSFT25 Immune/Hematopoietic 1963 HMSFW52 Immune/Hematopoietic 1964HMSGT73 Immune/Hematopoietic 1965 HMSGU30 Cancer 1966 HMSHB42 Cancer1967 HMSHB42 Cancer 1968 HMSHN72 Immune/Hematopoietic, Reproductive 1969HMSHT29 Immune/Hematopoietic 1970 HMSHW73 Immune/Hematopoietic 1971HMSIC48 Cardiovascular, Immune/Hematopoietic 1972 HMSII36Immune/Hematopoietic 1973 HMSIT42 Digestive, Immune/Hematopoietic,Neural/Sensory 1974 HMSJB08 Cancer 1975 HMSJI69 Immune/Hematopoietic1976 HMSJM20 Immune/Hematopoietic 1977 HMSJR44 Immune/Hematopoietic 1978HMSKQ91 Immune/Hematopoietic 1979 HMSKY45 Immune/Hematopoietic 1980HMTAF92 Cancer 1981 HMTAT36 Cancer 1982 HMUAB93 Cancer 1983 HMUAD65Immune/Hematopoietic, Musculoskeletal 1984 HMUAT23 Cancer 1985 HMUBA47Cancer 1986 HMUBJ22 Cancer 1987 HMUBK53 Cancer 1988 HMUBN24Musculoskeletal 1989 HMUBO15 Cancer 1990 HMUBX48 Musculoskeletal,Reproductive 1991 HMUBY57 Cancer 1992 HMUBZ15 Cancer 1993 HMVAL15 Cancer1994 HMVBC84 Digestive, Immune/Hematopoietic, Neural/Sensory 1995HMVBD68 Cancer 1996 HMVCG17 Immune/Hematopoietic 1997 HMVCS92 Cancer1998 HMVCS92 Cancer 1999 HMVDB45 Immune/Hematopoietic 2000 HMVDJ71Cancer 2001 HMVDT89 Cancer 2002 HMVDT89 Cancer 2003 HMWAO65 Cancer 2004HMWAO82 Immune/Hematopoietic 2005 HMWBD74 Cancer 2006 HMWBK35 Cancer2007 HMWBK86 Immune/Hematopoietic, Mixed Fetal 2008 HMWBL38Connective/Epithelial, Immune/Hematopoietic 2009 HMWBM48 Cancer 2010HMWCG28 Cancer 2011 HMWCP85 Digestive, Immune/Hematopoietic 2012 HMWDG30Cancer 2013 HMWDU20 Cancer 2014 HMWDX57 Digestive, Immune/Hematopoietic,Respiratory 2015 HMWDZ63 Immune/Hematopoietic 2016 HMWEA77Immune/Hematopoietic 2017 HMWEC03 Cancer 2018 HMWEF46Immune/Hematopoietic 2019 HMWEK43 Immune/Hematopoietic 2020 HMWEM23Cancer 2021 HMWEM23 Cancer 2022 HMWER46 Cancer 2023 HMWEU96 Cancer 2024HMWEX02 Cancer 2025 HMWFB65 Cancer 2026 HMWFD77 Immune/Hematopoietic2027 HMWFO25 Immune/Hematopoietic 2028 HMWFO89 Cancer 2029 HMWGM41Cancer 2030 HMWGO95 Immune/Hematopoietic 2031 HMWGV85 Cancer 2032HMWGZ42 Immune/Hematopoietic 2033 HMWHR36 Immune/Hematopoietic 2034HMWIM55 Immune/Hematopoietic 2035 HMWIQ26 Cancer 2036 HMWIU49 Cancer2037 HMWJJ62 Cancer 2038 HMWJJ64 Cancer 2039 HNAAD76 Digestive,Immune/Hematopoietic 2040 HNAAE24 Digestive 2041 HNALD94 Cancer 2042HNALE44 Cancer 2043 HNDAC35 Cancer 2044 HNEAA04 Immune/Hematopoietic2045 HNEAH26 Immune/Hematopoietic, Neural/Sensory 2046 HNEAK38Immune/Hematopoietic 2047 HNEAK65 Cancer 2048 HNEBX72Immune/Hematopoietic, Neural/Sensory 2049 HNEBY79 Immune/Hematopoietic2050 HNECD52 Immune/Hematopoietic, Neural/Sensory 2051 HNECL75 Cancer2052 HNECX90 Cancer 2053 HNECX90 Cancer 2054 HNEDA05Immune/Hematopoietic 2055 HNEDP75 Immune/Hematopoietic 2056 HNEDQ02Cancer 2057 HNEDU46 Cancer 2058 HNFAD50 Cancer 2059 HNFAD50 Cancer 2060HNFAG67 Cancer 2061 HNFCJ77 Immune/Hematopoietic, Reproductive 2062HNFCO56 Cancer 2063 HNFCY57 Connective/Epithelial, Immune/Hematopoietic,Respiratory 2064 HNFDL89 Digestive, Immune/Hematopoietic 2065 HNFDT73Excretory, Immune/Hematopoietic, Reproductive 2066 HNFDU92Immune/Hematopoietic 2067 HNFDY09 Digestive, Immune/Hematopoietic,Neural/Sensory 2068 HNFDY31 Cancer 2069 HNFEA17 Cancer 2070 HNFEP55Cancer 2071 HNFET12 Immune/Hematopoietic 2072 HNFFR59Immune/Hematopoietic 2073 HNFGC51 Cancer 2074 HNFGR15Immune/Hematopoietic 2075 HNFGW37 Immune/Hematopoietic 2076 HNFGW53Cancer 2077 HNFHA34 Cancer 2078 HNFHD58 Cancer 2079 HNFHV68Immune/Hematopoietic 2080 HNFIE15 Cancer 2081 HNFIE29Immune/Hematopoietic 2082 HNFIG49 Immune/Hematopoietic 2083 HNFJE27Immune/Hematopoietic 2084 HNFJG16 Immune/Hematopoietic 2085 HNGAC71Digestive, Immune/Hematopoietic 2086 HNGAK42 Immune/Hematopoietic 2087HNGAL25 Immune/Hematopoietic 2088 HNGAT83 Immune/Hematopoietic 2089HNGAX06 Cancer 2090 HNGBB09 Immune/Hematopoietic 2091 HNGBC53Immune/Hematopoietic 2092 HNGBD94 Immune/Hematopoietic 2093 HNGBE44Digestive, Immune/Hematopoietic 2094 HNGBE63 Immune/Hematopoietic 2095HNGBI83 Immune/Hematopoietic 2096 HNGBJ74 Immune/Hematopoietic 2097HNGBP30 Immune/Hematopoietic 2098 HNGBQ61 Immune/Hematopoietic 2099HNGBS35 Immune/Hematopoietic 2100 HNGBW25 Immune/Hematopoietic 2101HNGCF29 Immune/Hematopoietic 2102 HNGCF64 Immune/Hematopoietic 2103HNGDF54 Cancer 2104 HNGDH22 Immune/Hematopoietic 2105 HNGDH27Immune/Hematopoietic 2106 HNGDN07 Immune/Hematopoietic, Reproductive2107 HNGDO65 Cancer 2108 HNGDR39 Immune/Hematopoietic 2109 HNGDW78Immune/Hematopoietic 2110 HNGEA90 Immune/Hematopoietic 2111 HNGEC17Immune/Hematopoietic 2112 HNGEE06 Immune/Hematopoietic 2113 HNGEF70Immune/Hematopoietic 2114 HNGEF72 Immune/Hematopoietic 2115 HNGEI64Immune/Hematopoietic 2116 HNGEJ33 Cancer 2117 HNGEK64Immune/Hematopoietic 2118 HNGEN32 Immune/Hematopoietic 2119 HNGER85Immune/Hematopoietic 2120 HNGES90 Immune/Hematopoietic 2121 HNGET33Immune/Hematopoietic 2122 HNGEX18 Immune/Hematopoietic 2123 HNGEY45Immune/Hematopoietic 2124 HNGEZ02 Immune/Hematopoietic, Reproductive2125 HNGEZ90 Immune/Hematopoietic 2126 HNGFA25 Immune/Hematopoietic 2127HNGFB05 Immune/Hematopoietic 2128 HNGFD30 Immune/Hematopoietic, MixedFetal 2129 HNGFD31 Immune/Hematopoietic 2130 HNGFD61 Excretory,Immune/Hematopoietic 2131 HNGFG04 Immune/Hematopoietic 2132 HNGFG74Immune/Hematopoietic 2133 HNGFH32 Immune/Hematopoietic 2134 HNGFH83Immune/Hematopoietic 2135 HNGFI21 Cancer 2136 HNGFM31Immune/Hematopoietic 2137 HNGFN77 Immune/Hematopoietic 2138 HNGFQ18Immune/Hematopoietic 2139 HNGFR54 Immune/Hematopoietic 2140 HNGFT70Immune/Hematopoietic 2141 HNGFU70 Immune/Hematopoietic 2142 HNGFV39Immune/Hematopoietic 2143 HNGGF13 Immune/Hematopoietic 2144 HNGGK63Immune/Hematopoietic 2145 HNGGK65 Immune/Hematopoietic, Neural/Sensory,Reproductive 2146 HNGGL11 Immune/Hematopoietic 2147 HNGGO05Immune/Hematopoietic 2148 HNGGS92 Immune/Hematopoietic 2149 HNGGT10Cancer 2150 HNGGT74 Immune/Hematopoietic 2151 HNGHB89 Digestive,Immune/Hematopoietic, Reproductive 2152 HNGHD07 Immune/Hematopoietic2153 HNGHK37 Immune/Hematopoietic 2154 HNGHM47 Immune/Hematopoietic 2155HNGHT01 Immune/Hematopoietic, Neural/Sensory 2156 HNGHT86Immune/Hematopoietic 2157 HNGIH40 Immune/Hematopoietic 2158 HNGIK07Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal 2159HNGIM40 Immune/Hematopoietic 2160 HNGIM83 Immune/Hematopoietic 2161HNGIO93 Cancer 2162 HNGIS27 Immune/Hematopoietic 2163 HNGIU16Immune/Hematopoietic, Reproductive 2164 HNGIX91 Immune/Hematopoietic2165 HNGJA68 Immune/Hematopoietic 2166 HNGJB57 Immune/Hematopoietic 2167HNGJE86 Immune/Hematopoietic 2168 HNGJH26 Immune/Hematopoietic 2169HNGJJ61 Immune/Hematopoietic 2170 HNGJL07 Immune/Hematopoietic,Neural/Sensory 2171 HNGJS66 Immune/Hematopoietic, Reproductive 2172HNGJU60 Immune/Hematopoietic 2173 HNGKB09 Immune/Hematopoietic,Reproductive 2174 HNGKW35 Immune/Hematopoietic 2175 HNGKY94Immune/Hematopoietic 2176 HNGLD28 Immune/Hematopoietic 2177 HNGOY36Immune/Hematopoietic 2178 HNHAB38 Immune/Hematopoietic, Musculoskeletal2179 HNHAC43 Cancer 2180 HNHAD34 Immune/Hematopoietic 2181 HNHAG83Immune/Hematopoietic, Mixed Fetal, Musculoskeletal 2182 HNHAH06Immune/Hematopoietic 2183 HNHAJ65 Immune/Hematopoietic 2184 HNHAL61Immune/Hematopoietic 2185 HNHAP58 Cancer 2186 HNHAW34Immune/Hematopoietic 2187 HNHAW35 Immune/Hematopoietic 2188 HNHAY26Immune/Hematopoietic 2189 HNHAY86 Immune/Hematopoietic, Neural/Sensory2190 HNHAZ20 Immune/Hematopoietic 2191 HNHBE21 Immune/Hematopoietic 2192HNHBE38 Cancer 2193 HNHBG18 Immune/Hematopoietic 2194 HNHBI65Immune/Hematopoietic 2195 HNHBM16 Immune/Hematopoietic, Neural/Sensory2196 HNHCH78 Immune/Hematopoietic 2197 HNHCP14 Immune/Hematopoietic 2198HNHCQ44 Immune/Hematopoietic 2199 HNHCT22 Cardiovascular,Immune/Hematopoietic 2200 HNHCT47 Cardiovascular, Immune/Hematopoietic2201 HNHCV48 Immune/Hematopoietic 2202 HNHCZ54 Cancer 2203 HNHDC52Immune/Hematopoietic, Neural/Sensory 2204 HNHDD95 Immune/Hematopoietic2205 HNHDE58 Cancer 2206 HNHDI17 Immune/Hematopoietic 2207 HNHDL37Immune/Hematopoietic 2208 HNHDM21 Immune/Hematopoietic 2209 HNHDR57Immune/Hematopoietic 2210 HNHDR96 Immune/Hematopoietic 2211 HNHDU62Immune/Hematopoietic 2212 HNHDW34 Immune/Hematopoietic 2213 HNHDX28Immune/Hematopoietic 2214 HNHDZ06 Immune/Hematopoietic 2215 HNHDZ42Immune/Hematopoietic 2216 HNHEF37 Immune/Hematopoietic 2217 HNHEF49Immune/Hematopoietic 2218 HNHEF70 Immune/Hematopoietic 2219 HNHEG30Immune/Hematopoietic 2220 HNHEH38 Immune/Hematopoietic 2221 HNHEL22Immune/Hematopoietic 2222 HNHEN70 Cancer 2223 HNHEP21Immune/Hematopoietic 2224 HNHEP41 Immune/Hematopoietic 2225 HNHES33Immune/Hematopoietic, Reproductive 2226 HNHET16 Immune/Hematopoietic2227 HNHEY29 Immune/Hematopoietic 2228 HNHEZ76 Immune/Hematopoietic 2229HNHFF60 Immune/Hematopoietic 2230 HNHFF81 Immune/Hematopoietic,Neural/Sensory 2231 HNHFJ49 Immune/Hematopoietic 2232 HNHFR42Immune/Hematopoietic 2233 HNHFX25 Immune/Hematopoietic, Musculoskeletal2234 HNHGD95 Cardiovascular, Immune/Hematopoietic 2235 HNHGR82Immune/Hematopoietic 2236 HNHGS62 Immune/Hematopoietic 2237 HNHGY77Cancer 2238 HNHHA47 Digestive, Immune/Hematopoietic, Respiratory 2239HNHHN22 Immune/Hematopoietic 2240 HNHHW53 Immune/Hematopoietic 2241HNHIB40 Immune/Hematopoietic 2242 HNHKI74 Immune/Hematopoietic 2243HNHKV56 Immune/Hematopoietic 2244 HNHLD80 Immune/Hematopoietic 2245HNHLS76 Immune/Hematopoietic 2246 HNHLZ47 Immune/Hematopoietic 2247HNHMP15 Immune/Hematopoietic 2248 HNHMP62 Immune/Hematopoietic 2249HNHMY76 Immune/Hematopoietic, Reproductive 2250 HNHMZ01Immune/Hematopoietic 2251 HNHND14 Immune/Hematopoietic 2252 HNHND94Immune/Hematopoietic 2253 HNHOF09 Immune/Hematopoietic 2254 HNKAA76Cancer 2255 HNTAF42 Cancer 2256 HNTCG32 Cancer 2257 HNTNY89 Cancer 2258HNTRB25 Cancer 2259 HNTRQ40 Cancer 2260 HNTSQ23 Cancer 2261 HOAAH51Cancer 2262 HOAAI76 Cancer 2263 HOAAJ09 Cancer 2264 HOAAL10Musculoskeletal 2265 HOAAU13 Mixed Fetal, Musculoskeletal 2266 HOABC12Cancer 2267 HOABH36 Cancer 2268 HOBNA89 Musculoskeletal 2269 HOBNF51Cancer 2270 HODAH24 Reproductive 2271 HODAH46 Cancer 2272 HODAV25 Cancer2273 HODAW64 Cardiovascular, Neural/Sensory, Reproductive 2274 HODAY17Cancer 2275 HODBA45 Reproductive 2276 HODBC79 Cancer 2277 HODBD79Immune/Hematopoietic, Reproductive 2278 HODBF12 Cancer 2279 HODBF86Digestive, Reproductive 2280 HODBF91 Cancer 2281 HODBW34 Digestive,Immune/Hematopoietic, Reproductive 2282 HODBX93 Reproductive 2283HODBZ06 Cancer 2284 HODCA73 Cancer 2285 HODCV86 Immune/Hematopoietic,Reproductive 2286 HODCY44 Reproductive 2287 HODDB58 Neural/Sensory,Reproductive 2288 HODDG72 Cancer 2289 HODDJ25 Cancer 2290 HODDN21Reproductive 2291 HODDO31 Reproductive 2292 HODDQ06 Cancer 2293 HODEA20Cancer 2294 HODEM38 Digestive, Immune/Hematopoietic, Reproductive 2295HODET37 Reproductive 2296 HOEBI94 Cancer 2297 HOEBJ70 Cancer 2298HOECB33 Cancer 2299 HOECX21 Cancer 2300 HOEDE27 Musculoskeletal 2301HOEEK81 Cancer 2302 HOEEZ62 Musculoskeletal 2303 HOEFJ26 Cancer 2304HOEFL74 Cardiovascular, Digestive, Musculoskeletal 2305 HOFMF63 Cancer2306 HOFMJ65 Cancer 2307 HOFMK02 Immune/Hematopoietic, Reproductive 2308HOFMO16 Reproductive 2309 HOFMP62 Reproductive 2310 HOFMT59 Reproductive2311 HOFMV22 Reproductive 2312 HOFND06 Digestive, Reproductive 2313HOFNY15 Reproductive 2314 HOFNY28 Reproductive 2315 HOFOC41 Reproductive2316 HOGAA41 Cancer 2317 HOGAB51 Immune/Hematopoietic, Reproductive 2318HOGAH40 Cancer 2319 HOGAP06 Immune/Hematopoietic, Reproductive 2320HOGAR36 Reproductive 2321 HOGAR71 Cancer 2322 HOGCC26 Cancer 2323HOGCD78 Reproductive 2324 HOGCK03 Cancer 2325 HOGCL01 Cancer 2326HOHBB36 Cancer 2327 HOHBC57 Cancer 2328 HOHBO66 Cancer 2329 HOHBZ10Cancer 2330 HOHCH71 Cancer 2331 HOHEB48 Musculoskeletal 2332 HONAH67Digestive, Excretory, Reproductive 2333 HOOAC84 Immune/Hematopoietic,Neural/Sensory, Reproductive 2334 HOPBP13 Cancer 2335 HOQBG21 Cancer2336 HORBI80 Cancer 2337 HORBL77 Cancer 2338 HOSBX14Immune/Hematopoietic, Musculoskeletal, Reproductive 2339 HOSCZ41 Cancer2340 HOSEM81 Cancer 2341 HOSEO83 Cancer 2342 HOSFR35 Cancer 2343 HOUAZ32Cancer 2344 HOUBC29 Connective/Epithelial, Immune/Hematopoietic,Reproductive 2345 HOUBG39 Connective/Epithelial, Immune/Hematopoietic,Musculoskeletal 2346 HOUCD12 Connective/Epithelial 2347 HOUDB17Connective/Epithelial 2348 HOUDX40 Connective/Epithelial 2349 HOUEF84Cancer 2350 HOUEJ43 Connective/Epithelial 2351 HOUGS36Connective/Epithelial 2352 HOUHQ36 Connective/Epithelial 2353 HOUIG68Cancer 2354 HOUIG92 Cancer 2355 HOVAD93 Reproductive 2356 HOVAE10 Cancer2357 HOVAE36 Reproductive 2358 HOVAE82 Immune/Hematopoietic,Reproductive 2359 HOVAJ68 Reproductive 2360 HOVAW46 Musculoskeletal,Reproductive 2361 HOVBB19 Musculoskeletal, Reproductive 2362 HOVBD31Cancer 2363 HOVBE81 Reproductive 2364 HOVBI16 Cancer 2365 HOVBS68 Cancer2366 HOVCC73 Immune/Hematopoietic, Reproductive 2367 HOVCF30Immune/Hematopoietic, Reproductive 2368 HOVCJ71 Reproductive 2369HOVCN53 Reproductive 2370 HOVCO53 Reproductive 2371 HPASF94 Cancer 2372HPBCG26 Cancer 2373 HPBCT11 Reproductive 2374 HPBDE33 Cancer 2375HPBDE33 Cancer 2376 HPBDF31 Cancer 2377 HPCAG17 Immune/Hematopoietic,Reproductive 2378 HPCAG17 Immune/Hematopoietic, Reproductive 2379HPCAM02 Immune/Hematopoietic, Musculoskeletal, Reproductive 2380 HPDDQ17Endocrine 2381 HPDDQ28 Endocrine, Musculoskeletal 2382 HPDDT14 Cancer2383 HPEAA65 Digestive, Immune/Hematopoietic, Reproductive 2384 HPEAG24Cancer 2385 HPEBA84 Immune/Hematopoietic, Reproductive 2386 HPEBF91Cancer 2387 HPEBI09 Digestive, Reproductive 2388 HPFCJ75 Cancer 2389HPFCP75 Immune/Hematopoietic, Neural/Sensory, Reproductive 2390 HPFDB66Cancer 2391 HPFDD28 Reproductive 2392 HPFDI47 Digestive, Reproductive2393 HPIAF35 Reproductive 2394 HPIAK27 Cancer 2395 HPIAL55 Cancer 2396HPIAT18 Cancer 2397 HPIAZ52 Reproductive 2398 HPIBA07 Cancer 2399HPIBA24 Cancer 2400 HPIBI40 Cancer 2401 HPIBT19 Reproductive 2402HPJAA82 Reproductive 2403 HPJAB75 Cancer 2404 HPJAN76 Cancer 2405HPJAN76 Cancer 2406 HPJAU94 Immune/Hematopoietic, Reproductive 2407HPJAW78 Immune/Hematopoietic, Musculoskeletal, Reproductive 2408 HPJBS16Connective/Epithelial, Reproductive 2409 HPJBU04 Immune/Hematopoietic,Reproductive 2410 HPJCN83 Reproductive 2411 HPJCP75 Reproductive 2412HPJCV35 Reproductive 2413 HPJCX13 Cancer 2414 HPLAW13 Cancer 2415HPMAI31 Cancer 2416 HPMBI91 Reproductive 2417 HPMBT05 Reproductive 2418HPMBW95 Cancer 2419 HPMCW10 Cancer 2420 HPMCZ18 Cancer 2421 HPMDA80Cancer 2422 HPMDD27 Cancer 2423 HPMDF45 Excretory, Immune/Hematopoietic,Reproductive 2424 HPMDP57 Immune/Hematopoietic, Musculoskeletal,Reproductive 2425 HPMEG72 Cancer 2426 HPMFM70 Immune/Hematopoietic,Neural/Sensory, Reproductive 2427 HPMFP48 Cancer 2428 HPMFW01 Cancer2429 HPMGM06 Digestive, Neural/Sensory, Reproductive 2430 HPMGW43 Cancer2431 HPMGY89 Cancer 2432 HPMKB09 Cancer 2433 HPMSH26 Cancer 2434 HPMSH96Mixed Fetal, Reproductive 2435 HPQAJ25 Cardiovascular, Digestive, MixedFetal 2436 HPQAJ27 Cancer 2437 HPQAN50 Reproductive 2438 HPQAO80 Cancer2439 HPQAW27 Cancer 2440 HPQBC90 Cancer 2441 HPQBJ48 Cancer 2442 HPQBJ48Cancer 2443 HPQBL67 Cancer 2444 HPQBT17 Cancer 2445 HPQCF94 Cancer 2446HPQCI62 Cancer 2447 HPQRS74 Cancer 2448 HPRAD30 Cancer 2449 HPRCC91Cancer 2450 HPRCF40 Cancer 2451 HPRCF50 Cancer 2452 HPRCL58 Reproductive2453 HPRCM72 Cancer 2454 HPRCS59 Reproductive 2455 HPRCT73 Cancer 2456HPRTH56 Cancer 2457 HPTRE80 Cancer 2458 HPTRI42 Cancer 2459 HPTRL95Cancer 2460 HPTRQ52 Cancer 2461 HPTTH35 Cancer 2462 HPTTI65 Endocrine,Reproductive 2463 HPTTT62 Cancer 2464 HPTVH24 Cancer 2465 HPTVH59Endocrine, Neural/Sensory 2466 HPTVI04 Cancer 2467 HPTVI96 Cancer 2468HPVAA15 Cancer 2469 HPVAB20 Cancer 2470 HPVAB63 Cancer 2471 HPVAF86Reproductive 2472 HPWAH55 Digestive 2473 HPWAO89 Immune/Hematopoietic,Reproductive 2474 HPWAS27 Cancer 2475 HPWAT86 Immune/Hematopoietic,Neural/Sensory, Reproductive 2476 HPWAV82 Reproductive 2477 HPWBA36Reproductive 2478 HPWTF23 Cancer 2479 HPWTF23 Cancer 2480 HPWTF53 Cancer2481 HPXAB56 Immune/Hematopoietic 2482 HPZAB75 Digestive, Reproductive2483 HRAAB26 Excretory 2484 HRAAC36 Excretory, Immune/Hematopoietic 2485HRAAF59 Excretory 2486 HRAAG89 Cancer 2487 HRAAO40 Excretory 2488HRAAZ12 Cancer 2489 HRABA19 Excretory, Reproductive 2490 HRABP28Excretory, Immune/Hematopoietic 2491 HRABU56 Cardiovascular, Excretory,Musculoskeletal 2492 HRABZ80 Excretory, Immune/Hematopoietic,Musculoskeletal 2493 HRACB01 Excretory 2494 HRACI39 Excretory 2495HRADU15 Excretory 2496 HRDAH04 Immune/Hematopoietic, Mixed Fetal,Musculoskeletal 2497 HRDBA20 Musculoskeletal 2498 HRDBD32Musculoskeletal 2499 HRDBL01 Mixed Fetal, Musculoskeletal,Neural/Sensory 2500 HRDDM85 Musculoskeletal 2501 HRDDS22 Cancer 2502HRDEJ86 Cancer 2503 HRDEQ34 Musculoskeletal 2504 HRDFE30 Cancer 2505HRDFT83 Musculoskeletal 2506 HRGCA01 Musculoskeletal 2507 HRGCA06 Cancer2508 HRGSE38 Cancer 2509 HRLAT43 Cancer 2510 HRLME03 Cancer 2511 HROAN20Cardiovascular, Digestive 2512 HROAP64 Digestive 2513 HROAS35 Digestive2514 HROAY16 Digestive 2515 HROBJ10 Cancer 2516 HROBW46 Digestive,Immune/Hematopoietic 2517 HRODG86 Cancer 2518 HRSAL26 Cancer 2519HRTAE88 Digestive 2520 HRTAP63 Cancer 2521 HRTAR24 Digestive,Immune/Hematopoietic 2522 HSAAN03 Cancer 2523 HSAAS05Immune/Hematopoietic, Neural/Sensory 2524 HSAAW13 Cancer 2525 HSABA15Cancer 2526 HSABG81 Cancer 2527 HSATA50 Cardiovascular,Immune/Hematopoietic, Musculoskeletal 2528 HSATA61 Cancer 2529 HSATG66Cancer 2530 HSATI91 Immune/Hematopoietic 2531 HSATR50 Digestive,Immune/Hematopoietic, Reproductive 2532 HSATT82 Immune/Hematopoietic2533 HSATW19 Immune/Hematopoietic, Musculoskeletal 2534 HSATW67Excretory, Immune/Hematopoietic, Reproductive 2535 HSATZ02Immune/Hematopoietic, Musculoskeletal 2536 HSAUA95 Immune/Hematopoietic2537 HSAUB89 Cancer 2538 HSAUI53 Immune/Hematopoietic 2539 HSAUV74Cancer 2540 HSAUX39 Immune/Hematopoietic 2541 HSAVA58Immune/Hematopoietic, Mixed Fetal 2542 HSAVE52 Immune/Hematopoietic 2543HSAVH32 Immune/Hematopoietic 2544 HSAVM49 Immune/Hematopoietic 2545HSAVO11 Immune/Hematopoietic, Neural/Sensory 2546 HSAVO17Immune/Hematopoietic, Musculoskeletal 2547 HSAVQ13 Immune/Hematopoietic2548 HSAVR85 Cancer 2549 HSAVY92 Immune/Hematopoietic, Neural/Sensory2550 HSAVZ05 Digestive, Immune/Hematopoictic 2551 HSAWB58Immune/Hematopoietic 2552 HSAWH36 Immune/Hematopoietic 2553 HSAWM20Immune/Hematopoietic 2554 HSAWM74 Cancer 2555 HSAWX70 Cancer 2556HSAXC22 Immune/Hematopoietic 2557 HSAXI10 Digestive,Immune/Hematopoietic 2558 HSAXL49 Immune/Hematopoietic 2559 HSAXL82Immune/Hematopoietic 2560 HSAXN57 Immune/Hematopoietic 2561 HSAXO45Immune/Hematopoictic 2562 HSAXS06 Immune/Hematopoietic, Reproductive2563 HSAXS22 Immune/Hematopoietic 2564 HSAYL24 Immune/Hematopoietic 2565HSAYO82 Endocrine, Immune/Hematopoietic 2566 HSAYR62 Cancer 2567 HSAZP90Immune/Hematopoietic 2568 HSBAJ47 Cancer 2569 HSDBI90 Digestive,Endocrine, Neural/Sensory 2570 HSDDC55 Neural/Sensory 2571 HSDEA26Neural/Sensory 2572 HSDEY39 Neural/Sensory 2573 HSDFF72 Cancer 2574HSDFO08 Neural/Sensory 2575 HSDFR10 Digestive, Neural/Sensory,Reproductive 2576 HSDGB20 Neural/Sensory 2577 HSDGH56 Cancer 2578HSDGM01 Neural/Sensory 2579 HSDGM42 Cancer 2580 HSDGM42 Cancer 2581HSDGM42 Cancer 2582 HSDGM42 Cancer 2583 HSDGM42 Cancer 2584 HSDGM42Cancer 2585 HSDHD05 Neural/Sensory 2586 HSDIE51 Cancer 2587 HSDIK31Cancer 2588 HSDIV37 Cancer 2589 HSDJC96 Cancer 2590 HSDJE77Cardiovascular, Immune/Hematopoietic, Neural/Sensory 2591 HSDJF04 Cancer2592 HSDJG47 Cancer 2593 HSDJH72 Connective/Epithelial, Excretory,Neural/Sensory 2594 HSDJL07 Neural/Sensory, Reproductive 2595 HSDJR49Neural/Sensory 2596 HSDJV24 Cancer 2597 HSDJV40 Immune/Hematopoietic,Neural/Sensory 2598 HSDKA64 Immune/Hematopoietic, Neural/Sensory 2599HSDKE82 Neural/Sensory 2600 HSDKF96 Neural/Sensory 2601 HSDZO08 Cancer2602 HSDZQ96 Neural/Sensory 2603 HSEBB18 Cancer 2604 HSFAM19 Cancer 2605HSHAG54 Cancer 2606 HSHAS72 Cancer 2607 HSHAX04 Cancer 2608 HSHBT15Cancer 2609 HSHCE85 Cancer 2610 HSIAC81 Digestive 2611 HSIAF66 Digestive2612 HSIAP01 Digestive, Reproductive 2613 HSIDA33 Cancer 2614 HSIDA39Digestive 2615 HSIDZ25 Cancer 2616 HSIEB64 Digestive 2617 HSIEM18 Cancer2618 HSIFO61 Cancer 2619 HSIFO61 Cancer 2620 HSIGC63 Digestive,Immune/Hematopoietic, Reproductive 2621 HSIGM95 Digestive,Immune/Hematopoietic 2622 HSJAE76 Cancer 2623 HSJAN83 Digestive,Musculoskeletal 2624 HSJAQ10 Cancer 2625 HSJAR59 Musculoskeletal 2626HSJAU93 Cancer 2627 HSJAY14 Cancer 2628 HSJAY14 Cancer 2629 HSJAY14Cancer 2630 HSJAY14 Cancer 2631 HSJBB27 Musculoskeletal 2632 HSKBU03Musculoskeletal, Neural/Sensory 2633 HSKCQ51 Cancer 2634 HSKDE13 Cancer2635 HSKDS47 Cancer 2636 HSKHV81 Musculoskeletal 2637 HSKXB14 Cancer2638 HSKYR49 Cancer 2639 HSKYU81 Cancer 2640 HSKYY92 Musculoskeletal2641 HSLAB11 Cancer 2642 HSLAS96 Immune/Hematopoietic, Musculoskeletal2643 HSLAW59 Immune/Hematopoietic, Musculoskeletal 2644 HSLCH54 Cancer2645 HSLCH57 Cancer 2646 HSLCI86 Endocrine, Mixed Fetal, Musculoskeletal2647 HSLCS31 Cancer 2648 HSLCS34 Cancer 2649 HSLCV16 Cancer 2650 HSLDW54Cancer 2651 HSLEC18 Cancer 2652 HSLEG59 Musculoskeletal 2653 HSLFR59Cancer 2654 HSLGD91 Cancer 2655 HSLGF66 Cancer 2656 HSLGF70Musculoskeletal, Neural/Sensory 2657 HSLGP68 Musculoskeletal,Neural/Sensory 2658 HSNAB88 Cancer 2659 HSNAH56 Cancer 2660 HSNAN38Cancer 2661 HSNAO19 Cancer 2662 HSNAQ52 Cancer 2663 HSNAT08 Cancer 2664HSNAW06 Immune/Hematopoietic 2665 HSNAW37 Cancer 2666 HSNBJ05 Cancer2667 HSNBO90 Cancer 2668 HSNBQ36 Cancer 2669 HSNBS39 Cancer 2670 HSOAE34Digestive, Immune/Hematopoietic 2671 HSOAT44 Cancer 2672 HSOBB94 Cancer2673 HSOBH11 Digestive 2674 HSOBP75 Cancer 2675 HSOBW65 Digestive 2676HSPAA89 Digestive 2677 HSPAC13 Cancer 2678 HSPAG75 Digestive 2679HSPAI20 Digestive, Neural/Sensory 2680 HSPAL59 Digestive,Immune/Hematopoietic 2681 HSPAY90 Cancer 2682 HSPMF63 Cancer 2683HSQAC69 Cancer 2684 HSQAH14 Cancer 2685 HSQAX94 Cancer 2686 HSQBL20Cancer 2687 HSQCQ45 Cancer 2688 HSQCY74 Cancer 2689 HSQDM74 Cancer 2690HSQEG23 Cancer 2691 HSQEG47 Cancer 2692 HSQFE72 Cancer 2693 HSQFE76Cancer 2694 HSQFV12 Cancer 2695 HSRAA81 Cancer 2696 HSRAO56 Cancer 2697HSRAV28 Digestive, Musculoskeletal 2698 HSRDM56 Cancer 2699 HSRDW57Cancer 2700 HSREC72 Immune/Hematopoietic, Musculoskeletal 2701 HSREG42Cancer 2702 HSRFD18 Cancer 2703 HSRGZ11 Cancer 2704 HSRHB59 Cancer 2705HSSAN03 Cancer 2706 HSSCC66 Musculoskeletal 2707 HSSDI13 Musculoskeletal2708 HSSDQ20 Musculoskeletal, Neural/Sensory 2709 HSSDX38Musculoskeletal 2710 HSSED57 Cancer 2711 HSSEL28 Cancer 2712 HSSFP88Cancer 2713 HSSGS62 Musculoskeletal, Reproductive 2714 HSSJA23 Cancer2715 HSSJF26 Musculoskeletal 2716 HSSJF96 Musculoskeletal 2717 HSSJM47Cancer 2718 HSSJW30 Cancer 2719 HSSJW30 Cancer 2720 HSSJW30 Cancer 2721HSSMY35 Cancer 2722 HSTAL93 Connective/Epithelial 2723 HSTBG23Connective/Epithelial 2724 HSUAF06 Immune/Hematopoietic 2725 HSUBX67Immune/Hematopoietic 2726 HSUSB73 Immune/Hematopoietic, Reproductive2727 HSVAC05 Cancer 2728 HSVAE42 Connective/Epithelial, Neural/Sensory2729 HSVAL83 Cancer 2730 HSVAT36 Immune/Hematopoietic 2731 HSVAV02Cancer 2732 HSVBA83 Endocrine, Mixed Fetal 2733 HSVBD37 Cancer 2734HSVBN46 Cancer 2735 HSVBY62 Cancer 2736 HSVBZ53 Cancer 2737 HSVCF53Cardiovascular, Neural/Sensory, Reproductive 2738 HSWAZ17Connective/Epithelial, Reproductive, Respiratory 2739 HSWBI16 Cancer2740 HSXAI44 Neural/Sensory 2741 HSXAJ07 Neural/Sensory 2742 HSXAS59Neural/Sensory 2743 HSXAX20 Digestive, Mixed Fetal, Neural/Sensory 2744HSXAY60 Cancer 2745 HSXBB78 Neural/Sensory 2746 HSXCA83 Cancer 2747HSXCX20 Cancer 2748 HSXFG21 Cancer 2749 HSXFH82 Cancer 2750 HSYBD33Immune/Hematopoietic 2751 HSYBR79 Cancer 2752 HSYBV44Immune/Hematopoietic 2753 HSYBZ94 Cancer 2754 HT3AB13 Cancer 2755HT4SB02 Immune/Hematopoietic 2756 HT4SB37 Cardiovascular,Immune/Hematopoietic, Reproductive 2757 HT4SB81 Cancer 2758 HT4SB81Cancer 2759 HT4SB81 Cancer 2760 HT5FX76 Cancer 2761 HTABF81 Cancer 2762HTACX63 Immune/Hematopoietic 2763 HTADC63 Cancer 2764 HTADO61 Cancer2765 HTADQ22 Cancer 2766 HTAEC59 Cancer 2767 HTAED89Immune/Hematopoietic 2768 HTAEF02 Immune/Hematopoietic 2769 HTAEH58Immune/Hematopoietic 2770 HTAEO35 Immune/Hematopoietic 2771 HTDAF68Immune/Hematopoietic 2772 HTDAI38 Cancer 2773 HTEAJ87 Mixed Fetal,Neural/Sensory, Reproductive 2774 HTEAN76 Cancer 2775 HTEBL56 Cancer2776 HTECE87 Cancer 2777 HTEDF78 Reproductive 2778 HTEDT87 Cancer 2779HTEDX05 Cancer 2780 HTEEC19 Cancer 2781 HTEGH03 Cancer 2782 HTEGH03Cancer 2783 HTEGS48 Reproductive 2784 HTEGY81 Cancer 2785 HTEHB11Reproductive 2786 HTEHB49 Immune/Hematopoietic, Reproductive 2787HTEHS91 Cancer 2788 HTEHV60 Reproductive 2789 HTEHW80 Reproductive 2790HTEID25 Reproductive 2791 HTEIJ23 Cancer 2792 HTEIM62 Digestive,Immune/Hematopoietic, Reproductive 2793 HTEIV33 Reproductive 2794HTEIV65 Reproductive 2795 HTEJC50 Reproductive 2796 HTEJD20 Cancer 2797HTEJD61 Reproductive 2798 HTEJF31 Reproductive 2799 HTEJI29 Reproductive2800 HTEJL16 Reproductive 2801 HTEJP65 Cancer 2802 HTEJY20 Cancer 2803HTEKD35 Reproductive 2804 HTEKP82 Cardiovascular, Mixed Fetal,Reproductive 2805 HTEKV69 Reproductive 2806 HTEKZ52 Reproductive 2807HTEQG28 Immune/Hematopoietic, Reproductive 2808 HTFOB75 Cancer 2809HTGAA35 Immune/Hematopoietic 2810 HTGAD74 Immune/Hematopoietic,Reproductive 2811 HTGAP05 Immune/Hematopoietic, Neural/Sensory 2812HTGAQ29 Immune/Hematopoietic 2813 HTGAR21 Immune/Hematopoietic 2814HTGAS70 Cancer 2815 HTGAT65 Immune/Hematopoietic, Neural/Sensory,Reproductive 2816 HTGAU17 Immune/Hematopoietic 2817 HTGBF47Immune/Hematopoietic 2818 HTGBK95 Cancer 2819 HTGCC01Immune/Hematopoietic 2820 HTGCK43 Cancer 2821 HTGDS43Immune/Hematopoietic, Neural/Sensory 2822 HTGDS92 Cancer 2823 HTGEX34Digestive, Immune/Hematopoietic 2824 HTGFM31 Immune/Hematopoietic 2825HTGGM37 Digestive, Immune/Hematopoietic 2826 HTGGN22Immune/Hematopoietic 2827 HTHAA41 Cancer 2828 HTHBC58 Digestive,Immune/Hematopoietic 2829 HTHBO72 Cancer 2830 HTHBQ29Immune/Hematopoietic 2831 HTHBT76 Cancer 2832 HTHBZ91Immune/Hematopoietic 2833 HTHCA30 Cancer 2834 HTHCM60Immune/Hematopoietic 2835 HTHDB20 Immune/Hematopoietic 2836 HTHDF45Immune/Hematopoietic 2837 HTHDF86 Immune/Hematopoietic 2838 HTHDH18Immune/Hematopoietic 2839 HTHDP65 Cancer 2840 HTHDT25Immune/Hematopoietic 2841 HTHDV50 Immune/Hematopoietic 2842 HTJMA64Cancer 2843 HTJMJ72 Connective/Epithelial, Immune/Hematopoietic 2844HTLAD74 Reproductive 2845 HTLAF81 Cancer 2846 HTLBF46 Cancer 2847HTLBF63 Cancer 2848 HTLCX82 Cancer 2849 HTLDD89 Reproductive 2850HTLDN34 Reproductive 2851 HTLDP19 Cancer 2852 HTLDY30 Cancer 2853HTLEJ24 Cancer 2854 HTLEJ75 Cancer 2855 HTLEJ75 Cancer 2856 HTLEP55Cancer 2857 HTLEV80 Cancer 2858 HTLEZ57 Cancer 2859 HTLFA90 Cancer 2860HTLGL33 Reproductive 2861 HTLGQ25 Reproductive 2862 HTLGS72 Reproductive2863 HTLGY50 Cancer 2864 HTLHN86 Cancer 2865 HTLHN86 Cancer 2866 HTLHN86Cancer 2867 HTLHN86 Cancer 2868 HTLIW29 Cancer 2869 HTLJC15 Cancer 2870HTNAL14 Cancer 2871 HTNAL34 Endocrine, Reproductive 2872 HTNBJ15 Cancer2873 HTNBJ15 Cancer 2874 HTNBJ15 Cancer 2875 HTNBJ15 Cancer 2876 HTOAC65Immune/Hematopoietic 2877 HTOAE47 Immune/Hematopoietic 2878 HTOAK03Cancer 2879 HTOAO58 Immune/Hematopoietic 2880 HTOAT56 Cancer 2881HTOBG07 Immune/Hematopoietic, Musculoskeletal 2882 HTOBG62Immune/Hematopoietic 2883 HTODA92 Cancer 2884 HTODN35Immune/Hematopoietic 2885 HTODO45 Immune/Hematopoietic 2886 HTOEA53Digestive, Excretory, Immune/Hematopoietic 2887 HTOEB55 Cancer 2888HTOEB76 Immune/Hematopoietic 2889 HTOET03 Cancer 2890 HTOET03 Cancer2891 HTOEV01 Immune/Hematopoietic, Reproductive 2892 HTOFA11 Cancer 2893HTOFC33 Immune/Hematopoietic 2894 HTOGB79 Cancer 2895 HTOHE22Immune/Hematopoietic 2896 HTOHG63 Cancer 2897 HTOHJ93Immune/Hematopoietic 2898 HTOHM12 Immune/Hematopoietic, Neural/Sensory2899 HTOHM82 Cancer 2900 HTOHN40 Immune/Hematopoietic, Neural/Sensory2901 HTOHR59 Digestive, Immune/Hematopoietic, Neural/Sensory 2902HTOHS29 Cancer 2903 HTOID65 Cancer 2904 HTOIE17 Excretory,Immune/Hematopoietic 2905 HTOIG16 Immune/Hematopoietic, Reproductive2906 HTOIH39 Immune/Hematopoietic 2907 HTOIH51 Immune/Hematopoietic 2908HTOJB02 Immune/Hematopoietic 2909 HTOJJ26 Connective/Epithelial,Digestive, Immune/Hematopoietic 2910 HTOJP25 Immune/Hematopoietic 2911HTOJS23 Immune/Hematopoietic 2912 HTOJY56 Cancer 2913 HTOJZ18Immune/Hematopoietic 2914 HTPCG10 Cancer 2915 HTPCO75 Cancer 2916HTPCW21 Digestive, Neural/Sensory 2917 HTPDD68 Cancer 2918 HTPDV75Digestive, Reproductive 2919 HTSER28 Cancer 2920 HTSET62 Cancer 2921HTSFV18 Cancer 2922 HTSGO13 Cancer 2923 HTSGO88 Immune/Hematopoietic2924 HTTAH05 Reproductive 2925 HTTAP37 Immune/Hematopoietic,Reproductive 2926 HTTBJ38 Cancer 2927 HTTDB11 Cancer 2928 HTTDG27Reproductive 2929 HTTDN24 Cancer 2930 HTTDO33 Cancer 2931 HTTDT67 Cancer2932 HTTEO25 Cancer 2933 HTTEP11 Neural/Sensory, Reproductive 2934HTTES77 Cancer 2935 HTTFD29 Reproductive 2936 HTTFG15 Cancer 2937HTWAM19 Immune/Hematopoietic 2938 HTWBF58 Immune/Hematopoietic 2939HTWBO30 Cancer 2940 HTWBZ57 Cancer 2941 HTWCC10 Immune/Hematopoietic2942 HTWCE14 Cancer 2943 HTWCT76 Digestive, Immune/Hematopoietic 2944HTWDJ17 Cancer 2945 HTWDM89 Immune/Hematopoietic 2946 HTWEA05Immune/Hematopoietic 2947 HTWEG06 Immune/Hematopoietic 2948 HTWEQ36Cancer 2949 HTWFA21 Immune/Hematopoietic 2950 HTWFA88 Digestive,Immune/Hematopoietic 2951 HTWFM85 Cancer 2952 HTWFO43 Cancer 2953HTWLG39 Cancer 2954 HTXAA20 Cancer 2955 HTXAD75 Cancer 2956 HTXAR92Immune/Hematopoietic 2957 HTXBS38 Cancer 2958 HTXBU88Immune/Hematopoietic 2959 HTXCP27 Cancer 2960 HTXCU30 Excretory,Immune/Hematopoietic 2961 HTXCV44 Immune/Hematopoietic, Neural/Sensory2962 HTXDJ21 Immune/Hematopoietic 2963 HTXDJ75 Digestive,Immune/Hematopoietic, Mixed Fetal 2964 HTXDJ85 Immune/Hematopoietic 2965HTXDK09 Cancer 2966 HTXDO17 Immune/Hematopoietic, Neural/Sensory,Respiratory 2967 HTXDT72 Cancer 2968 HTXDU08 Cancer 2969 HTXDZ68Immune/Hematopoietic, Musculoskeletal 2970 HTXEN33 Immune/Hematopoietic,Reproductive 2971 HTXES13 Cancer 2972 HTXFD86 Cancer 2973 HTXGK12 Cancer2974 HTXGL32 Immune/Hematopoietic 2975 HTXJD08 Digestive,Immune/Hematopoietic 2976 HTXJD85 Immune/Hematopoietic 2977 HTXJE12Cancer 2978 HTXJI59 Cancer 2979 HTXJJ92 Cancer 2980 HTXJM94 Cancer 2981HTXJV54 Digestive, Immune/Hematopoietic, Reproductive 2982 HTXJW06Cancer 2983 HTXKB57 Cancer 2984 HTXKH22 Immune/Hematopoietic 2985HTXKH40 Cancer 2986 HTXKK76 Immune/Hematopoietic 2987 HTXKL53 Cancer2988 HTXKS11 Immune/Hematopoietic 2989 HTXKS27 Cancer 2990 HTXLC05Digestive, Immune/Hematopoietic, Respiratory 2991 HTXLC45Immune/Hematopoietic 2992 HTXLT36 Cancer 2993 HTXLY94 Cancer 2994HTXNV66 Cancer 2995 HTXOL30 Immune/Hematopoietic 2996 HTXOW27 Cancer2997 HTXPD86 Cancer 2998 HTXPT57 Digestive, Immune/Hematopoietic 2999HTYSJ88 Endocrine, Immune/Hematopoietic 3000 HUDBE20 Reproductive 3001HUDBK47 Immune/Hematopoietic, Reproductive 3002 HUFAB57 Cancer 3003HUFAL17 Digestive 3004 HUFAO92 Digestive, Reproductive 3005 HUFAO94Cancer 3006 HUFAP33 Cancer 3007 HUFAU71 Cancer 3008 HUFBK95 Digestive,Reproductive 3009 HUFBP77 Cancer 3010 HUFBV62 Cancer 3011 HUFBY96 Cancer3012 HUFCN72 Digestive 3013 HUFEF79 Cancer 3014 HUKAD46 Endocrine,Immune/Hematopoietic, Reproductive 3015 HUKAI28 Cardiovascular,Reproductive 3016 HUKAO50 Cancer 3017 HUKCS86 Cancer 3018 HUKCS86 Cancer3019 HUKEA22 Cancer 3020 HUKEL79 Cancer 3021 HUKEX37 Reproductive 3022HUKFC71 Cancer 3023 HUKFV37 Cancer 3024 HUKFY09 Cancer 3025 HUNAL39Reproductive 3026 HUSAO04 Cancer 3027 HUSAO04 Cancer 3028 HUSCA09 Cancer3029 HUSCJ01 Cancer 3030 HUSGB23 Cancer 3031 HUSGJ09 Cardiovascular,Neural/Sensory 3032 HUSGQ57 Cancer 3033 HUSGY15 Cancer 3034 HUSHD41Cancer 3035 HUSHK65 Cancer 3036 HUSIK45 Cancer 3037 HUSIO57 Cancer 3038HUSIP17 Cardiovascular 3039 HUSIR70 Cancer 3040 HUSXP50 Cardiovascular,Reproductive 3041 HUSXY93 Cancer 3042 HUSYG26 Cancer 3043 HUVCQ68 Cancer3044 HUVDG58 Digestive, Immune/Hematopoietic, Reproductive 3045 HUVEG53Cancer 3046 HWAAH11 Cancer 3047 HWAAQ28 Cancer 3048 HWAAY60 Cancer 3049HWABR43 Digestive, Immune/Hematopoietic 3050 HWACH06 Cancer 3051 HWACZ33Digestive, Immune/Hematopoietic, Reproductive 3052 HWADV90Immune/Hematopoietic 3053 HWAEB52 Cancer 3054 HWBAK71Immune/Hematopoietic 3055 HWBBU75 Cancer 3056 HWBCN81Immune/Hematopoietic, Reproductive 3057 HWBCP16 Immune/Hematopoietic3058 HWBCX93 Cancer 3059 HWBEF34 Immune/Hematopoietic, Neural/Sensory3060 HWFBB23 Cancer 3061 HWFBI40 Connective/Epithelial, Digestive,Immune/Hematopoietic 3062 HWHGV77 Connective/Epithelial 3063 HWHGW09Cancer 3064 HWHHA21 Connective/Epithelial 3065 HWHPU44Connective/Epithelial 3066 HWHRC51 Cancer 3067 HWLAT50 Cancer 3068HWLBO67 Digestive 3069 HWLGP26 Cancer 3070 HWLHO31 Cardiovascular,Digestive 3071 HWLIL31 Cancer 3072 HWLJN08 Cancer 3073 HWLRE03 Cancer3074 HWTAM38 Digestive, Immune/Hematopoietic, Reproductive 3075 HWTAW58Cancer 3076 HWTBB42 Cancer 3077 HWTBC75 Cancer 3078 HWTBI25 Cancer 3079HWTBL86 Cancer 3080 HWTBX66 Cancer 3081 HYAAC74 Immune/Hematopoietic,Musculoskeletal, Reproductive 3082 HYAAD61 Immune/Hematopoietic 3083HYACC21 Immune/Hematopoietic 3084 HYBAP75 Cancer 3085 HYBAQ24 Cancer3086 HYBAW56 Musculoskeletal 3087 HYBBD81 Musculoskeletal

Table 1E provides information related to biological activities andpreferred indications for polynucleotides and polypeptides of theinvention (including antibodies, agonists, and/or antagonists thereof).Table 1E also provides information related to assays which may be usedto test polynucleotides and polypeptides of the invention (includingantibodies, agonists, and/or antagonists thereof) for the correspondingbiological activities. The first column (“Gene No.”) provides the genenumber in the application for each clone identifier. The second column(“cDNA Clone ID:”) provides the unique clone identifier for each cloneas previously described and indicated in Tables 1A, 1B, 1C, and 1D. Thethird column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ IDNumber for polypeptide sequences encoded by the corresponding cDNAclones (also as indicated in Tables 1A, 1B, and 2). The fourth column(“Biological Activity”) indicates a biological activity corresponding tothe indicated polypeptides (or polynucleotides encoding saidpolypeptides). The fifth column (“Exemplary Activity Assay”) furtherdescribes the corresponding biological activity and also providesinformation pertaining to the various types of assays which may beperformed to test, demonstrate, or quantify the corresponding biologicalactivity. The sixth column (“Preferred Indictions”) describes particularembodiments of the invention as well as indications (e.g. pathologies,diseases, disorders, abnormalities, etc.) for which polynucleotides andpolypeptides of the invention (including antibodies, agonists, and/orantagonists thereof) may be used in detecting, diagnosing, preventing,and/or treating.

Table 1E describes the use of, inter alia, FMAT technology for testingor demonstrating various biological activities. Fluorometric microvolumeassay technology (FMAT) is a fluorescence-based system which provides ameans to perform nonradioactive cell- and bead-based assays to detectactivation of cell signal transduction pathways. This technology wasdesigned specifically for ligand binding and immunological assays. Usingthis technology, fluorescent cells or beads at the bottom of the wellare detected as localized areas of concentrated fluorescence using adata processing system. Unbound flurophore comprising the backgroundsignal is ignored, allowing for a wide variety of homogeneous assays.FMAT technology may be used for peptide ligand binding assays,immunofluorescence, apoptosis, cytotoxicity, and bead-basedimmunocapture assays. See, Miraglia S et. al., “Homogeneous cell andbead based assays for highthroughput screening using flourometricmicrovolume assay technology,” Journal of Biomolecular Screening;4:193-204 (1999). In particular, FMAT technology may be used to test,confirm, and/or identify the ability of polypeptides (includingpolypeptide fragments and variants) to activate signal transductionpathways. For example, FMAT technology may be used to test, confirm,and/or identify the ability of polypeptides to upregulate production ofimmunomodulatory proteins (such as, for example, interleukins, GM-CSF,Rantes, and Tumor Necrosis factors, as well as other cellular regulators(e.g. insulin)).

Table 1E also describes the use of kinase assays for testing,demonstrating, or quantifying biological activity. In this regard, thephosphorylation and de-phosphorylation of specific amino acid residues(e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteinsprovides a fast, reversible means for activation and de-activation ofcellular signal transduction pathways. Moreover, cell signaltransduction via phosphorylation/de-phosphorylation is crucial to theregulation of a wide variety of cellular processes (e.g. proliferation,differentiation, migration, apoptosis, etc.). Accordingly, kinase assaysprovide a powerful tool useful for testing, confirming, and/oridentifying polypeptides (including polypeptide fragments and variants)that mediate cell signal transduction events via proteinphosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R.“Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38Kinase Activities” Biol. Chem. 379(8-9): 1101-1110 (1998). LENGTHY TABLEREFERENCED HERE US20070048297A1-20070301-T00005 Please refer to the endof the specification for access instructions.Table 1F:

Polynucleotides encoding polypeptides of the present invention can beused in assays to test for one or more biological activities. One suchbiological activity which may be tested includes the ability ofpolynucleotides and polypeptides of the invention to stimulateup-regulation or down-regulation of expression of particular genes andproteins. Hence, if polynucleotides and polypeptides of the presentinvention exhibit activity in altering particular gene and proteinexpression patterns, it is likely that these polynucleotides andpolypeptides of the present invention may be involved in, or capable ofeffecting changes in, diseases associated with the altered gene andprotein expression profiles. Hence, polynucleotides, polypeptides, orantibodies of the present invention could be used to treat saidassociated diseases.

TaqMan® assays may be performed to assess the ability of polynucleotides(and polypeptides they encode) to alter the expression pattern ofparticular “target” genes. TaqMan® reactions are performed to evaluatethe ability of a test agent to induce or repress expression of specificgenes in different cell types. TaqMan® gene expression quantificationassays (“TaqMan® assays”) are well known to, and routinely performed by,those of ordinary skill in the art. TaqMan® assays are performed in atwo step reverse transcription/polymerase chain reaction (RT-PCR). Inthe first (RT) step, cDNA is reverse transcribed from total RNA samplesusing random hexamer primers. In the second (PCR) step, PCR products aresynthesized from the cDNA using gene specific primers.

To quantify gene expression the Taqman® PCR reaction exploits the 5′nuclease activity of AmpliTaq Gold® DNA Polymerase to cleave a Taqman®probe (distinct from the primers) during PCR. The Taqman® probe containsa reporter dye at the 5′-end of the probe and a quencher dye at the 3′end of the probe. When the probe is intact, the proximity of thereporter dye to the quencher dye results in suppression of the reporterfluorescence. During PCR, if the target of interest is present, theprobe specifically anneals between the forward and reverse primer sites.AmpliTaq Fold DNA Polymerase then cleaves the probe between the reporterand quencher when the probe hybridizes to the target, resulting inincreased fluorescence of the reporter (see FIG. 2). Accumulation of PCRproducts is detected directly by monitoring the increase in fluorescenceof the reporter dye.

After the probe fragments are displaced from the target, polymerizationof the strand continues. The 3′-end of the probe is blocked to preventextension of the probe during PCR. This process occurs in every cycleand does not interfere with the exponential accumulation of product. Theincrease in fluorescence signal is detected only if the target sequenceis complementary to the probe and is amplified during PCR. Because ofthese requirements, any nonspecific amplification is not detected.

For test sample preparation, vector controls or constructs containingthe coding sequence for the gene of interest are transfected into cells,such as for example 293T cells, and supernatants collected after 48hours. For cell treatment and RNA isolation, multiple primary humancells or human cell lines are used; such cells may include but are notlimited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, HumanUmbilical Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, andTHP-1 cell lines. Cells are plated in growth media and growth isarrested by culturing without media change for 3 days, or by switchingcells to low serum media and incubating overnight. Cells are treated for1, 6, or 24 hours with either vector control supernatant or samplesupernatant (or purified/partially purified protein preparations inbuffer). Total RNA is isolated; for example, by using Trizol extractionor by using the Ambion RNAqueous™-4PCR RNA isolation system. Expressionlevels of multiple genes are analyzed using Taqman®, and expression inthe test sample is compared to control vector samples to identify genesinduced or repressed. Each of the above described techniques are wellknown to, and routinely performed by, those of ordinary skill in theart.

Table 1F indicates particular disease classes and preferred indicationsfor which polynucleotides, polypeptides, or antibodies of the presentinvention may be used in detecting, diagnosing, preventing, treatingand/or ameliorating said diseases and disorders based on “target” geneexpression patterns which may be up- or down-regulated bypolynucleotides (and the encoded polypeptides) corresponding to eachindicated cDNA Clone ID (shown in Table 1F, Column 2).

Thus, in preferred embodiments, the present invention encompasses amethod of detecting, diagnosing, preventing, treating, and/orameliorating a disease or disorder listed in the “Disease Class” and/or“Preferred Indication” columns of Table 1F; comprising administering toa patient in which such detection, diagnosis, prevention, or treatmentis desired a protein, nucleic acid, or antibody of the invention (orfragment or variant thereof) in an amount effective to detect, diagnose,prevent, treat, or ameliorate the disease or disorder. The first andsecond columns of Table 1D show the “Gene No.” and “cDNA Clone ID No.”,respectively, indicating certain nucleic acids and proteins (orantibodies against the same) of the invention (including polynucleotide,polypeptide, and antibody fragments or variants thereof) that may beused in detecting, diagnosing, preventing, treating, or ameliorating thedisease(s) or disorder(s) indicated in the corresponding row in the“Disease Class” or “Preferred Indication” Columns of Table 1F.

In another embodiment, the present invention also encompasses methods ofdetecting, diagnosing, preventing, treating, or ameliorating a diseaseor disorder listed in the “Disease Class” or “Preferred Indication”Columns of Table 1F; comprising administering to a patient combinationsof the proteins, nucleic acids, or antibodies of the invention (orfragments or variants thereof), sharing similar indications as shown inthe corresponding rows in the “Disease Class” or “Preferred Indication”Columns of Table 1F.

The “Disease Class” Column of Table 1F provides a categorizeddescriptive heading for diseases, disorders, and/or conditions (morefully described below) that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Preferred Indication” Column of Table 1F describes diseases,disorders, and/or conditions that may be detected, diagnosed, prevented,treated, or ameliorated by a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof).

The “Cell Line” and “Exemplary Targets” Columns of Table 1F indicateparticular cell lines and target genes, respectively, which may showaltered gene expression patterns (i.e., up- or down-regulation of theindicated target gene) in Taqman® assays, performed as described above,utilizing polynucleotides of the cDNA Clone ID shown in thecorresponding row. Alteration of expression patterns of the indicated“Exemplary Target” genes is correlated with a particular “Disease Class”and/or “Preferred Indication” as shown in the corresponding row underthe respective column headings.

The “Exemplary Accessions” Column indicates GenBank Accessions(available online through the National Center for BiotechnologyInformation (NCBI) at http://www.ncbi.nlm.nih.gov/) which correspond tothe “Exemplary Targets” shown in the adjacent row.

The recitation of “Cancer” in the “Disease Class” Column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof) may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorateneoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., asdescribed below under “Hyperproliferative Disorders”).

The recitation of “Immune” in the “Disease Class” column indicates thatthe corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, prevent, treat, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), blood disorders (e.g., asdescribed below under “Immune Activity” “Cardiovascular Disorders”and/or “Blood-Related Disorders”), and infections (e.g., as describedbelow under “Infectious Disease”).

The recitation of “Angiogenesis” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diseasesand/or disorders relating to neoplastic diseases (e.g., as describedbelow under “Hyperproliferative Disorders”), diseases and/or disordersof the cardiovascular system (e.g., as described below under“Cardiovascular Disorders”), diseases and/or disorders involvingcellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), diseases and/or disorders involvingangiogenesis (e.g., as described below under “Anti-AngiogenesisActivity”), to promote or inhibit cell or tissue regeneration (e.g., asdescribed below under “Regeneration”), or to promote wound healing(e.g., as described below under “Wound Healing and Epithelial CellProliferation”).

The recitation of “Diabetes” in the “Disease Class” column indicatesthat the corresponding nucleic acid and protein, or antibody against thesame, of the invention (or fragment or variant thereof), may be used forexample, to detect, diagnose, treat, prevent, and/or ameliorate diabetes(including diabetes mellitus types I and II), as well as diseases and/ordisorders associated with, or consequential to, diabetes (e.g. asdescribed below under “Endocrine Disorders,” “Renal Disorders,” and“Gastrointestinal Disorders”). TABLE 1F Gene cDNA Disease Exemplary No.Clone ID Class Preferred Indications Cell Line Targets ExemplaryAccessions 423 HTEEW69 Immune Highly preferred indications include AOSMCCCR7 gb|X84702|HSDNABLR2 immunological disorders such as describedherein CXCR3 gb|Z79783|HSCKRL2 under the heading “Immune Activity”and/or Rag2 gb|AY011962|AY011962 “Blood-Related Disorders” (particularlyVLA4 gb|X16983|HSINTAL4 including, but not limited to, immune disordersinvolving muscle tissues and the cardiovascular system (e.g. heart,lungs, circulatory system)). Highly preferred embodiments of theinvention include methods of preventing, detecting, diagnosing, treatingand/or ameliorating disorders of the immune system (particularlyincluding, but not limited to, immune disorders involving muscle tissueor the cardiovascular system). (AOSMC cells are human aortic smoothmuscle cells). 423 HTEEW69 Immune Highly preferred indications includeCaco-2 TNF gb|AJ270944|HSA27094 immunological disorders such asdescribed herein under the heading “Immune Activity” and/or“Blood-Related Disorders” (particularly including, but not limited to,immune disorders involving the cells of the gastrointestinal tract).Highly preferred embodiments of the invention include methods ofpreventing, detecting, diagnosing, treating and/or amelioratingdisorders of the immune system (particularly including, but not limitedto, immune disorders involving cells of the gastrointestinal tract).(The Caco-2 cell line is a human colorectal adenocarcinoma cell lineavailable through the ATCC as cell line number HTB-37). 423 HTEEW69Immune Highly preferred indications include Daudi GATA3gb|X55037|HSGATA3 immunological disorders such as described herein ICAMgb|X06990|HSICAM1 under the heading “Immune Activity” and/or TNFgb|AJ270944|HSA27094 “Blood-Related Disorders” (particularly including,but not limited to, immune disorders involving the B-cells). Highlypreferred embodiments of the invention include methods of preventing,detecting, diagnosing, treating and/or ameliorating disorders of theimmune system (particularly including, but not limited to, immunedisorders involving B-cells). (The Daudi cell line is a human Blymphoblast cell line available through the ATCC as cell line numberCCL-213). 423 HTEEW69 Immune Highly preferred indications include HEK293TNF gb|AJ270944|HSA27094 immunological disorders such as describedherein under the heading “Immune Activity” and/or “Blood-RelatedDisorders” (particularly including, but not limited to, immune disordersinvolving epithelial cells or the renal system). Highly preferredembodiments of the invention include methods of preventing, detecting,diagnosing, treating and/or ameliorating disorders of the immune system(particularly including, but not limited to, immune disorders involvingepithelial cells or the renal system). (The 293 cell line is a humanembryonal kidney epithelial cell line available through the ATCC as cellline number CRL-1573). 423 HTEEW69 Immune Highly preferred indicationsinclude Liver ICAM gb|X06990|HSICAM1 immunological disorders such asdescribed herein under the heading “Immune Activity” and/or“Blood-Related Disorders” (particularly including, but not limited to,immune disorders involving cells of the hepatic system). Highlypreferred embodiments of the invention include methods of preventing,detecting, diagnosing, treating and/or ameliorating disorders of theimmune system (particularly including, but not limited to, immunedisorders involving cells of the hepatic system). 423 HTEEW69 ImmuneHighly preferred indications include NHDF CIS3 gb|AB006967|AB006967immunological disorders such as described herein TNFgb|AJ270944|HSA27094 under the heading “Immune Activity” and/or“Blood-Related Disorders” (particularly including, but not limited to,immune disorders involving the skin). Highly preferred embodiments ofthe invention include methods of preventing, detecting, diagnosing,treating and/or ameliorating disorders of the immune system(particularly including, but not limited to, immune disorders involvingthe skin). (NHDF cells are normal human dermal fibroblasts). 423 HTEEW69Immune Highly preferred indications include SK-N-MC TNFgb|AJ270944|HSA27094 immunological disorders such as described hereinneuroblastoma VCAM gb|A30922|A30922 under the heading “Immune Activity”and/or “Blood-Related Disorders” (particularly including, but notlimited to, immune disorders involving the central nervous system).Highly preferred embodiments of the invention include methods ofpreventing, detecting, diagnosing, treating and/or amelioratingdisorders of the immune system (particularly including, but not limitedto, immune disorders involving the central nervous sytem). (The SK-N-MCneuroblastoma cell line is a cell line derived from human brain tissueand is available through the ATCC as cell line number HTB-10). 423HTEEW69 Immune Highly preferred indications include THP1 CD25gb|X03137|HSIL2RG7 immunological disorders such as described herein CD40gb|AJ300189|HSA30018 under the heading “Immune Activity” and/or GATA3gb|X55037|HSGATA3 “Blood-Related Disorders” (particularly LTBRgb|AK027080|AK027080 including, but not limited to, immune disordersRag1 gb|M29474|HUMRAG1 involving monocytes). Highly preferredembodiments of the invention include methods of preventing, detecting,diagnosing, treating and/or ameliorating disorders of the immune system(particularly including, but not limited to, immune disorders involvingmonocytes). (The THP1 cell line is a human monocyte cell line availablethrough the ATCC as cell line number TIB-202). 423 HTEEW69 Immune Highlypreferred indications include U937 IL1B gb|X02532|HSIL1BR immunologicaldisorders such as described herein TNF gb|AJ270944|HSA27094 under theheading “Immune Activity” and/or “Blood-Related Disorders” (particularlyincluding, but not limited to, immune disorders involving monocytes).Highly preferred embodiments of the invention include methods ofpreventing, detecting, diagnosing, treating and/or amelioratingdisorders of the immune system (particularly including, but not limitedto, immune disorders involving monocytes). (The U937 cell line is ahuman monocyte cell line available through the ATCC; cell #CRL-1593.2).878 HCEGG08 Immune Highly preferred indications include AOSMC CIS3gb|AB006967|AB006967 immunological disorders such as described hereinGranzyme gb|J04071|HUMCSE under the heading “Immune Activity” and/or B“Blood-Related Disorders” (particularly IL1B gb|X02532|HSIL1BRincluding, but not limited to, immune disorders IL5 gb|X12705|HSBCDFIAinvolving muscle tissues and the cardiovascular system (e.g. heart,lungs, circulatory system)). Highly preferred embodiments of theinvention include methods of preventing, detecting, diagnosing, treatingand/or ameliorating disorders of the immune system (particularlyincluding, but not limited to, immune disorders involving muscle tissueor the cardiovascular system). (AOSMC cells are human aortic smoothmuscle cells). 878 HCEGG08 Immune Highly preferred indications includeHEK293 ICAM gb|X06990|HSICAM1 immunological disorders such as describedherein under the heading “Immune Activity” and/or “Blood-RelatedDisorders” (particularly including, but not limited to, immune disordersinvolving epithelial cells or the renal system). Highly preferredembodiments of the invention include methods of preventing, detecting,diagnosing, treating and/or ameliorating disorders of the immune system(particularly including, but not limited to, immune disorders involvingepithelial cells or the renal system). (The 293 cell line is a humanembryonal kidney epithelial cell line available through the ATCC as cellline number CRL-1573). 878 HCEGG08 Immune Highly preferred indicationsinclude HUVEC CCR7 gb|X84702|HSDNABLR2 immunological disorders such asdescribed herein TNF gb|AJ270944|HSA27094 under the heading “ImmuneActivity” and/or “Blood-Related Disorders” (particularly including, butnot limited to, immune disorders involving endothelial cells). Highlypreferred embodiments of the invention include methods of preventing,detecting, diagnosing, treating and/or ameliorating disorders of theimmune system (particularly including, but not limited to, immunedisorders involving endothelial cells). (HUVEC cells are human umbilicalvein endothelial cells). 878 HCEGG08 Immune Highly preferred indicationsinclude Jurkat GATA1 gb|X17254|HSERYF1 immunological disorders such asdescribed herein Rag1 gb|M29474|HUMRAG1 under the heading “ImmuneActivity” and/or Rag2 gb|AY011962|AY011962 “Blood-Related Disorders”(particularly including, but not limited to, immune disorders involvingT-cells). Highly preferred embodiments of the invention include methodsof preventing, detecting, diagnosing, treating and/or amelioratingdisorders of the immune system (particularly including, but not limitedto, immune disorders involving T-cells). (The Jurkat cell line is ahuman T lymphocyte cell line available through the ATCC; cell line#TIB-152). 878 HCEGG08 Immune Highly preferred indications include LiverICAM gb|X06990|HSICAM1 immunological disorders such as described hereinunder the heading “Immune Activity” and/or “Blood-Related Disorders”(particularly including, but not limited to, immune disorders involvingcells of the hepatic system). Highly preferred embodiments of theinvention include methods of preventing, detecting, diagnosing, treatingand/or ameliorating disorders of the immune system (particularlyincluding, but not limited to, immune disorders involving cells of thehepatic system). 878 HCEGG08 Immune Highly preferred indications includeNHDF HLA-c immunological disorders such as described herein under theheading “Immune Activity” and/or “Blood-Related Disorders” (particularlyincluding, but not limited to, immune disorders involving the skin).Highly preferred embodiments of the invention include methods ofpreventing, detecting, diagnosing, treating and/or amelioratingdisorders of the immune system (particularly including, but not limitedto, immune disorders involving the skin). (NHDF cells are normal humandermal fibroblasts). 878 HCEGG08 Immune Highly preferred indicationsinclude SK-N-MC HLA-c immunological disorders such as described hereinneuroblastoma VCAM gb|A30922|A30922 under the heading “Immune Activity”and/or “Blood-Related Disorders” (particularly including, but notlimited to, immune disorders involving the central nervous system).Highly preferred embodiments of the invention include methods ofpreventing, detecting, diagnosing, treating and/or amelioratingdisorders of the immune system (particularly including, but not limitedto, immune disorders involving the central nervous sytem). (The SK-N-MCneuroblastoma cell line is a cell line derived from human brain tissueand is available through the ATCC as cell line number HTB-10). 878HCEGG08 Immune Highly preferred indications include THP1 CCR3gb|AB023887|AB023887 immunological disorders such as described hereinCCR4 gb|AB023888|AB023888 under the heading “Immune Activity” and/orCTLA4 gb|AF316875|AF316875 “Blood-Related Disorders” (particularlyGranzyme gb|J04071|HUMCSE including, but not limited to, immunedisorders B involving monocytes). Highly preferred Rag2gb|AY011962|AY011962 embodiments of the invention include methods ofVCAM gb|A30922|A30922 preventing, detecting, diagnosing, treating and/orameliorating disorders of the immune system (particularly including, butnot limited to, immune disorders involving monocytes). (The THP1 cellline is a human monocyte cell line available through the ATCC as cellline number TIB-202). 878 HCEGG08 Immune Highly preferred indicationsinclude U937 CCR5 gb|AF161918|AF161918 immunological disorders such asdescribed herein CCR7 gb|X84702|HSDNABLR2 under the heading “ImmuneActivity” and/or CD25 gb|X03137|HSIL2RG7 “Blood-Related Disorders”(particularly CD30 including, but not limited to, immune disorders CXCR3gb|Z79783|HSCKRL2 involving monocytes). Highly preferred Rag1gb|M29474|HUMRAG1 embodiments of the invention include methods of Rag2gb|AY011962|AY011962 preventing, detecting, diagnosing, treating and/orameliorating disorders of the immune system (particularly including, butnot limited to, immune disorders involving monocytes). (The U937 cellline is a human monocyte cell line available through the ATCC as cellline number CRL-1593.2).

Table 2 further characterizes certain encoded polypeptides of theinvention, by providing the results of comparisons to protein andprotein family databases. The first column provides a unique cloneidentifier, “Clone ID NO:”, corresponding to a cDNA clone disclosed inTable 1A and/or Table 1B. The second column provides the unique contigidentifier, “Contig ID:” which allows correlation with the informationin Table 1B. The third column provides the sequence identifier, “SEQ IDNO:”, for the contig polynucleotide sequences. The fourth columnprovides the analysis method by which the homology/identity disclosed inthe Table was determined. The fifth column provides a description of thePFAM/NR hit identified by each analysis. Column six provides theaccession number of the PFAM/NR hit disclosed in the fifth column.Column seven, score/percent identity, provides a quality score or thepercent identity, of the hit disclosed in column five. Comparisons weremade between polypeptides encoded by polynucleotides of the inventionand a non-redundant protein database (herein referred to as “NR”), or adatabase of protein families (herein referred to as “PFAM”), asdescribed below.

The NR database, which comprises the NBRF PIR database, the NCBI GenPeptdatabase, and the SIB SwissProt and TrEMBL databases, was madenon-redundant using the computer program nrdb2 (Warren Gish, WashingtonUniversity in Saint Louis). Each of the polynucleotides shown in Table1B, column 3 (e.g., SEQ ID NO:X or the ‘Query’ sequence) was used tosearch against the NR database. The computer program BLASTX was used tocompare a 6-frame translation of the Query sequence to the NR database(for information about the BLASTX algorithm please see Altshul et al.,J. Mol. Biol. 215:403-410 (1990), and Gish and States, Nat. Genet.3:266-272 (1993). A description of the sequence that is most similar tothe Query sequence (the highest scoring ‘Subject’) is shown in columnfive of Table 2 and the database accession number for that sequence isprovided in column six. The highest scoring ‘Subject’ is reported inTable 2 if (a) the estimated probability that the match occurred bychance alone is less than 1.0 e-07, and (b) the match was not to a knownrepetitive element. BLASTX returns alignments of short polypeptidesegments of the Query and Subject sequences which share a high degree ofsimilarity; these segments are known as High-Scoring Segment Pairs orHSPs. Table 2 reports the degree of similarity between the Query and theSubject for each HSP as a percent identity in Column 7. The percentidentity is determined by dividing the number of exact matches betweenthe two aligned sequences in the HSP, dividing by the number of Queryamino acids in the HSP and multiplying by 100. The polynucleotides ofSEQ ID NO:X which encode the polypeptide sequence that generates an HSPare delineated by columns 8 and 9 of Table 2.

The PFAM database, PFAM version 2.1, (Sonnhammer, Nucl. Acids Res.,26:320-322, 1998)) consists of a series of multiple sequence alignments;one alignment for each protein family. Each multiple sequence alignmentis converted into a probability model called a Hidden Markov Model, orHMM, that represents the position-specific variation among the sequencesthat make up the multiple sequence alignment (see, e.g., Durbin, et al.,Biological sequence analysis: probabilistic models of proteins andnucleic acids, Cambridge University Press, 1998 for the theory of HMMs).The program HMMER version 1.8 (Sean Eddy, Washington University in SaintLouis) was used to compare the predicted protein sequence for each Querysequence (SEQ ID NO:Y in Table 1B.1) to each of the HMMs derived fromPFAM version 2.1. A HMM derived from PFAM version 2.1 was said to be asignificant match to a polypeptide of the invention if the scorereturned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 scoreobtained with the most distantly related known member of that proteinfamily. The description of the PFAM family which shares a significantmatch with a polypeptide of the invention is listed in column 5 of Table2, and the database accession number of the PFAM hit is provided incolumn 6. Column 7 provides the score returned by HMMER version 1.8 forthe alignment. Columns 8 and 9 delineate the polynucleotides of SEQ IDNO:X which encode the polypeptide sequence which show a significantmatch to a PFAM protein family.

As mentioned, columns 8 and 9 in Table 2, “NT From” and “NT To”,delineate the polynucleotides of “SEQ ID NO:X” that encode a polypeptidehaving a significant match to the PFAM/NR database as disclosed in thefifth column. In one embodiment, the invention provides a proteincomprising, or alternatively consisting of, a polypeptide encoded by thepolynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2.Also provided are polynucleotides encoding such proteins, and thecomplementary strand thereto.

The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y aresufficiently accurate and otherwise suitable for a variety of uses wellknown in the art and described further below. For instance, thenucleotide sequences of SEQ ID NO:X are useful for designing nucleicacid hybridization probes that will detect nucleic acid sequencescontained in SEQ ID NO:X or the cDNA contained in ATCC Deposit No: Z.These probes will also hybridize to nucleic acid molecules in biologicalsamples, thereby enabling immediate applications in chromosome mapping,linkage analysis, tissue identification and/or typing, and a variety offorensic and diagnostic methods of the invention. Similarly,polypeptides identified from SEQ ID NO:Y may be used to generateantibodies which bind specifically to these polypeptides, or fragmentsthereof, and/or to the polypeptides encoded by the cDNA clonesidentified in, for example, Table 1A and/or 1B.

Nevertheless, DNA sequences generated by sequencing reactions cancontain sequencing errors. The errors exist as misidentifiednucleotides, or as insertions or deletions of nucleotides in thegenerated DNA sequence. The erroneously inserted or deleted nucleotidescause frame shifts in the reading frames of the predicted amino acidsequence. In these cases, the predicted amino acid sequence divergesfrom the actual amino acid sequence, even though the generated DNAsequence may be greater than 99.9% identical to the actual DNA sequence(for example, one base insertion or deletion in an open reading frame ofover 1000 bases).

Accordingly, for those applications requiring precision in thenucleotide sequence or the amino acid sequence, the present inventionprovides not only the generated nucleotide sequence identified as SEQ IDNO:X, and a predicted translated amino acid sequence identified as SEQID NO:Y, but also a sample of plasmid DNA containing cDNA ATCC DepositNo: Z (e.g., as set forth in columns 2 and 3 of Table 1A and/or as setforth, for example, in Table 1B, 6, and 7). The nucleotide sequence ofeach deposited clone can readily be determined by sequencing thedeposited clone in accordance with known methods. Further, techniquesknown in the art can be used to verify the nucleotide sequences of SEQID NO:X.

The predicted amino acid sequence can then be verified from suchdeposits. Moreover, the amino acid sequence of the protein encoded by aparticular clone can also be directly determined by peptide sequencingor by expressing the protein in a suitable host cell containing thedeposited human cDNA, collecting the protein, and determining itssequence. TABLE 2 SEQ PFam/NR Score/ cDNA ID Analysis Accession PercentNT Clone ID Contig ID: NO: X Method PFam/NR Description Number IdentityFrom NT To H6BSF56 762968 11 HMMER PFAM: Zinc-binding dehydrogenasesPF00107 35.6 176 415 2.1.1 WUblastx.64 (Q9BV79) SIMILAR TO CGI-63 Q9BV79100% 25 42 PROTEIN. 92% 53 427 H6EDM64 841331 12 WUblastx.64 (Q9UID3)ANG2. Q9UID3 90% 928 2451 36% 203 310 36% 931 1038 95% 191 871 H6EEC72889401 13 WUblastx.64 hypothetical protein DKFZp434L061.1 -pir|T43456|T43456 80% 1484 1203 human 41% 1277 1080 35% 973 845 34% 659549 57% 991 365 HACBJ56 847112 15 WUblastx.64 (Q9D2Q2) 2310079F23RIKQ9D2Q2 65% 98 286 PROTEIN. HACBS22 847113 16 WUblastx.64 (O60266)ADENYLATE CYCLASE CYA3_HUMAN 89% 6 416 TYPE III (EC 4.6.1.1) (ADENYLATE25% 1547 2299 18% 917 1111 93% 416 2449 HADMB15 847116 19 WUblastx.64(Q9BVH1) SIMILAR TO DLXIN-1. Q9BVH1 100% 8 109 HAGEG10 823543 22WUblastx.64 (Q9NWT5) CDNA FLJ20618 FIS, Q9NWT5 100% 1237 1377 CLONEKAT05049. 96% 1 156 HAGFS57 847120 24 WUblastx.64 (Q9Y485) X-LIKE 1PROTEIN. Q9Y485 58% 9 872 HAGHN57 773286 25 WUblastx.64 (O60416) WUGSC:H_RG276O03.2 O60416 98% 65 1444 PROTEIN. HAHEA15 847013 26 WUblastx.64(Q9NWD5) HYPOTHETICAL 31.4 KDA Q9NWD5 76% 455 832 PROTEIN. 99% 30 560HAJAA47 534670 27 WUblastx.64 (Q9NZA3) CDA14. Q9NZA3 100% 17 157 HAJAY92845601 28 WUblastx.64 (O00549) ORF2-LIKE PROTEIN O00549 53% 2226 2318(FRAGMENT). 26% 769 915 38% 1653 1769 31% 1721 2242 HAJBV67 866415 29WUblastx.64 (Q9HD45) TRANSMEMBRANE 9 T9S3_HUMAN 100% 13 126 SUPERFAMILYPROTEIN 93% 116 1681 MEMBER 3 PRECU HAOAG15 852204 31 HMMER PFAM: vonWillebrand factor type A PF00092 180.1 506 1057 2.1.1 domain WUblastx.64(O75578) INTEGRIN ALPHA-10 ITAG_HUMAN 90% 8 3463 PRECURSOR. HAQCE11633730 33 WUblastx.64 (Q24333) ELASTIN LIKE PROTEIN Q24333 95% 61 132(FRAGMENT). HATCB45 631172 35 WUblastx.64 (Q9D0I6) 2610014F08RIKPROTEIN. Q9D0I6 88% 490 645 HATCI03 580805 37 WUblastx.64 (Q9H743) CDNA:FLJ21394 FIS, Q9H743 71% 906 688 CLONE COL03536. HBAGD86 838799 39WUblastx.64 (Q14287) HYPOTHETICAL Q14287 37% 801 559 PROTEIN (FRAGMENT).HBDAB91 789532 41 WUblastx.64 (O00370) PUTATIVE P150. O00370 40% 587 51334% 529 5 HBDAB91 864374 42 WUblastx.64 (O00370) PUTATIVE P150. O0037040% 907 833 35% 849 307 HBGBC29 691473 43 WUblastx.64 (O60513) BETA-1,4-B4G4_HUMAN 61% 1 78 GALACTOSYLTRANSFERASE 4 98% 65 1021 (EC 2.4.1.—)(BET HBHAA05 603174 45 WUblastx.64 (Q9H387) PRO2550. Q9H387 71% 676 386HBHAA81 846465 46 WUblastx.64 (Q9D1G3) 1110011D13RIK Q9D1G3 89% 13291502 PROTEIN. 79% 28 1329 HBIAC29 831751 48 WUblastx.64 (Q9D7J5)2310005N01RIK Q9D7J5 78% 25 492 PROTEIN. 93% 883 927 HBJAB02 837309 50WUblastx.64 (Q9NXT6) CDNA FLJ20062 FIS, Q9NXT6 70% 2 1210 CLONECOL01508. HBJCR46 815649 53 HMMER PFAM: WD domain, G-beta repeat PF0040036.6 790 867 2.1.1 WUblastx.64 (Q9DC22) 1200006M05RIK Q9DC22 96% 207 611PROTEIN. 73% 568 2763 HBJDS79 813588 54 WUblastx.64 (Q9CY11)2510039O18RIK Q9CY11 92% 1119 1325 PROTEIN. 89% 1322 1519 93% 1032 1127100% 1509 1532 66% 2 1075 HBJEL16 847030 56 WUblastx.64 (O95297) PROTEINZERO O95297 98% 285 491 RELATED PROTEIN. HBJIG20 866159 58 HMMER PFAM:Cytochrome c oxidase subunit PF00510 162.6 321 551 2.1.1 III WUblastx.64(BAA77671) Cytochrome c oxidase BAA77671 81% 9 617 subunit 3 (FragmentHBJKD16 853358 59 WUblastx.64 (Q9NXS4) CDNA FLJ20080 FIS, Q9NXS4 91% 81528 CLONE COL03184. HBMBM96 561935 60 WUblastx.64 (Q9H387) PRO2550.Q9H387 69% 661 494 67% 794 639 HBMTX26 695704 63 WUblastx.64 (Q14288)HYPOTHETICAL Q14288 46% 964 608 PROTEIN (FRAGMENT). 61% 272 156 66% 136101 54% 611 507 58% 546 292 HBMTY48 637521 64 WUblastx.64 (Q9H5N9) CDNA:FLJ23235 FIS, Q9H5N9 94% 54 941 CLONE CAS04980. HBMUH74 866160 65WUblastx.64 (Q9NVW8) CDNA FLJ10462 FIS, Q9NVW8 100% 11 427 CLONENT2RP1001494, WEAKLY SIMILAR TO MAL HBMWE61 778066 66 WUblastx.64(Q9BX88) MAGPHININ DELTA. Q9BX88 100% 302 520 95% 869 1009 HBNAX40834801 67 WUblastx.64 (Q9H2K2) TANKYRASE-LIKE Q9H2K2 100% 1 201 PROTEIN(TANKYRASE 2). 100% 221 481 HBQAB79 810542 69 WUblastx.64 (Q9UQ32) AD 3(FRAGMENT). Q9UQ32 82% 323 204 HBSAK32 856387 71 WUblastx.64 (Q9H1Q7)BA12M19.1.3 (NOVEL Q9H1Q7 100% 239 412 PROTEIN). 100% 95 172 HBXCM66639039 72 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 65% 988 809CLONE COL04765. 77% 836 690 HBXCX15 637542 73 WUblastx.64 (Q9GMX5)HYPOTHETICAL 12.9 KDA Q9GMX5 41% 726 827 PROTEIN. 52% 578 730 HCDCY76837972 74 WUblastx.64 frizzled protein 4 - human pir|JC7127|JC7127 100%1039 527 30% 994 785 79% 567 37 HCE1G78 761204 76 HMMER PFAM: Inositolpolyphosphate PF00783 277.3 77 775 2.1.1 phosphatase family, catalyticdomain WUblastx.64 (Q9UDT9) WUGSC: H_DJ412A9.2 Q9UDT9 72% 8 1549 PROTEIN(FRAGMENT). 95% 8 67 HCE2H52 847007 77 WUblastx.64 probabletransposase - human pir|S72481|S72481 60% 564 758 transposon MER37 77%430 537 75% 754 1251 HCE3B04 831151 78 WUblastx.64 (O43466) HYPOTHETICAL31.3 KDA O43466 98% 836 1003 PROTEIN (FRAGMENT). 45% 217 972 HCEDR26771144 80 WUblastx.64 (Q9H919) CDNA FLJ13078 FIS, Q9H919 66% 1157 1095CLONE NT2RP3002002. 66% 1345 1184 HCEEQ25 531784 82 WUblastx.64 (P78349)SODIUM CHANNEL 2. P78349 95% 311 433 93% 433 480 100% 658 714 HCEEU18688041 83 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 49% 186 10PRODUCT. 56% 1223 933 HCEFZ82 831745 84 WUblastx.64 (Q9BV23) SIMILAR TOLIPASE Q9BV23 95% 594 782 PROTEIN. 100% 17 604 HCFLN88 610000 86WUblastx.64 (Q9BQE9) SIMILAR TO B-CELL Q9BQE9 87% 278 475 CLL/LYMPHOMA7B (UNKNOWN) (PROTEIN FOR MGC HCFLT90 788578 87 WUblastx.64 (Q9CVC2)2210013O21RIK Q9CVC2 53% 612 445 PROTEIN (FRAGMENT). 70% 850 671 HCHAB84834326 88 WUblastx.64 (Q9BRV3) STROMAL CELL Q9BRV3 89% 82 744 PROTEIN.HCNSD29 862314 91 WUblastx.64 (O75400) HUNTINGTIN- O75400 82% 628 1605INTERACTING PROTEIN 78% 337 489 HYPA/FBP11 (FRAGMENT). HCRAY10 695709 96WUblastx.64 (AAH08671) Similar to RIKEN cDNA AAH08671 77% 72 4405530601I19 gene. HCRBF72 828945 97 WUblastx.64 (Q9UI95) MITOTIC SPINDLEMD22_HUMAN 94% 191 823 ASSEMBLY CHECKPOINT PROTEIN MAD2B HCUCF89 637986100 WUblastx.64 (Q9P147) PRO2822. Q9P147 100% 421 398 82% 494 426HCUCK44 790277 101 WUblastx.64 hypothetical protein DKFZp564J157.1 -pir|T34520|T34520 100% 29 157 human (fragment) 100% 377 403 HDPDI72897277 109 WUblastx.64 adult-specific brush border protein -pir|C45665|C45665 64% 180 230 rabbit 83% 11 100 HDPDJ58 587265 110WUblastx.64 hypothetical protein pir|T42691|T42691 100% 307 609DKFZp434D2328.1 - human 87% 621 785 (fragment) 36% 101 313 36% 307 60636% 188 316 42% 89 172 27% 23 307 85% 14 307 37% 134 307 35% 101 307 35%89 274 32% 137 307 36% 325 594 34% 543 671 38% 307 606 37% 322 585 28%307 606 29% 358 606 33% 337 594 41% 487 594 37% 92 307 36% 352 606 32%89 316 32% 340 594 30% 83 316 35% 454 606 31% 654 785 41% 624 779 31%624 794 40% 630 785 34% 624 776 33% 630 785 34% 83 307 35% 92 286 34%1229 1402 36% 1265 1411 36% 660 785 32% 624 779 39% 645 773 35% 645 78535% 645 785 32% 785 1393 34% 280 606 36% 259 594 32% 259 591 32% 319 591100% 1405 1464 33% 322 510 33% 633 881 29% 656 1327 25% 902 1402 30% 8481402 30% 1040 1420 36% 89 307 39% 827 1042 41% 962 1117 27% 803 1402 33%131 307 25% 848 1144 27% 89 307 37% 125 307 30% 854 1447 76% 746 1450HDPFF10 853513 111 HMMER PFAM: Leucine Rich Repeat PF00560 65.1 729 8002.1.1 WUblastx.64 garp precursor - human pir|S42799|S42799 38% 285 96542% 1153 1593 32% 1306 1641 29% 1147 1446 31% 1614 1898 26% 1159 151230% 1174 1536 33% 1306 1632 30% 1174 1494 31% 1162 1539 33% 1183 150028% 468 893 27% 246 965 37% 1629 2111 HDPFU43 790189 112 WUblastx.64(AAH01057) Tyrosylprotein AAH01057 100% 360 1349 sulfotransferase 2. 58%220 348 HDPGE24 801947 114 WUblastx.64 (Q9P195) PRO1722. Q9P195 65% 14131291 43% 1388 1278 77% 2528 2394 47% 2182 2078 75% 1774 1751 62% 26042557 68% 1301 1167 HDPIU94 813352 115 WUblastx.64 (Q9BVF7) SIMILAR TOQ9BVF7 99% 63 1703 HYPOTHETICAL PROTEIN FLJ10422. HDPOC24 777493 116WUblastx.64 (Q9H8K1) CDNA FLJ13518 FIS, Q9H8K1 100% 62 208 CLONEPLACE1005799. HDPOL37 745377 117 WUblastx.64 (AAK40301) TRH4. AAK4030170% 502 323 60% 1325 483 HDPPQ30 684292 120 WUblastx.64 (Q9H387)PRO2550. Q9H387 51% 807 727 79% 1042 815 HDPPW82 778405 121 WUblastx.64hypothetical protein UL126 - human pir|S09875|S09875 94% 6 116cytomegalovirus (strain AD169) HDQHM36 852328 123 WUblastx.64 (Q9N083)UNNAMED PORTEIN Q9N083 69% 1129 1257 PRODUCT. 50% 965 1153 HDTAU35838139 124 WUblastx.64 (Q9T9V8) NADH Q9T9V8 87% 56 175 DEHYDROGENASESUBUNIT 3. 83% 305 340 HDTAV54 801898 125 WUblastx.64 (AAH01231)Glutathione S-transferase AAH01231 100% 13 303 subunit 13 hom HDTGW48827285 127 WUblastx.64 (Q9P1W8) SIRP-B2. Q9P1W8 100% 783 1100 79% 13591757 HE2CA60 888705 130 WUblastx.64 (O95232) OKADAIC ACID- OA48_HUMAN98% 1098 1265 INDUCIBLE PHOSPHOPROTEIN OA48-18. HE2HC60 753265 133WUblastx.64 (Q9NVC4) CDNA FLJ10814 FIS, Q9NVC4 88% 125 1300 CLONENT2RP4000984. HE6CS65 762960 136 WUblastx.64 (Q9H7C6) CDNA: FLJ21047FIS, Q9H7C6 98% 938 1378 CLONE CAS00253. HE6DO92 562767 137 WUblastx.64gag polyprotein - human endogenous pir|A46312|A46312 63% 623 895 virusS71 80% 19 633 HE6EY13 847058 138 WUblastx.64 (O95476) HYPOTHETICAL 28.3KDA O95476 92% 5 472 PROTEIN. HE6FU11 827236 139 HMMER PFAM: vonWillebrand factor type A PF00092 184.7 244 771 2.1.1 domain WUblastx.64(O95460) MATRILIN-4 MTN4_HUMAN 77% 145 789 PRECURSOR. 45% 782 907 41%791 925 50% 794 907 38% 863 1498 33% 190 741 98% 782 1642 HE8FC45 843781141 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 50% 1285 1172 CLONEKAIA0536. 57% 1824 1663 75% 1672 1553 HE8FC45 845672 142 WUblastx.64(Q9NX85) CDNA FLJ20378 FIS, Q9NX85 50% 1285 1172 CLONE KAIA0536. 57%1824 1663 75% 1672 1553 HE8FD92 856544 145 WUblastx.64 (Q9UJI9)HYPOTHETICAL 105.9 KDA Q9UJI9 84% 419 1414 PROTEIN. 71% 2 1060 76% 4191345 61% 2 613 45% 203 1060 40% 449 1345 52% 2 328 33% 605 1345 46% 47328 HE8FD92 869847 146 WUblastx.64 (Q9UJI9) HYPOTHETICAL 105.9 KDAQ9UJI9 74% 4 609 PROTEIN. 59% 4 540 50% 1 255 63% 346 540 63% 346 54060% 346 540 49% 1 255 48% 1 255 53% 346 540 41% 4 255 33% 40 255 HE8FD92901142 147 WUblastx.64 (Q9UJI9) HYPOTHETICAL 105.9 KDA Q9UJI9 76% 31 480PROTEIN. 56% 31 411 67% 217 408 67% 217 408 63% 217 411 63% 217 411 60%217 411 53% 217 411 59% 31 126 56% 31 126 56% 31 126 56% 31 126 39% 58126 HE8SG96 862016 148 WUblastx.64 (Q9P195) PRO1722. Q9P195 58% 19971845 63% 1854 1687 HE8TY46 899528 149 WUblastx.64 (BAB55144) CDNAFLJ14576 fis, BAB55144 95% 318 938 clone NT2RM4001092, w HE9CY05 834826150 WUblastx.64 (Q9CX63) 6030468B19RIK Q9CX63 48% 434 742 PROTEIN. 57%55 426 HE9EA10 827796 151 WUblastx.64 laminin alpha-1 chain precursor -pir|S14458|S14458 99% 761 1891 human 27% 878 1840 25% 1142 1876 HEBFR46847064 157 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 80% 1111 1022CLONE KAIA0536. 84% 1265 1110 HEBGE07 798096 158 WUblastx.64 (Q9NX85)CDNA FLJ20378 FIS, Q9NX85 79% 1851 1720 CLONE KAIA0536. HELAT35 693175160 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 72% 2092 1802 CLONECOL04765. HELBU54 637624 161 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS,Q9H728 59% 1255 1031 CLONE COL04765. HEMEY47 834491 164 WUblastx.64(Q9H387) PRO2550. Q9H387 68% 513 587 74% 578 838 HEPBA14 855935 166WUblastx.64 (Q9BTY9) UNKNOWN (PROTEIN Q9BTY9 87% 423 515 FOR IMAGE:2823490) 71% 15 77 (FRAGMENT). 92% 85 426 HEQAH80 701984 167 WUblastx.64(Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 60% 818 1045 PROTEIN. HEQBF89786205 168 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 64% 793 638CLONE COL04765. 64% 647 489 HETCI16 844543 169 WUblastx.64 (Q9P0V3)BOG25. Q9P0V3 99% 3 356 HETDW58 790557 170 WUblastx.64 unidentified27.6K protein, spliced pir|JC7586|JC7586 95% 324 1058 form A - humanHFCFE20 701985 175 WUblastx.64 (Q9CSE5) EUKARYOTIC Q9CSE5 89% 438 581TRANSLATION INITIATION 54% 1083 1187 FACTOR 3 (FRAGMENT). HFEAY59 658685176 WUblastx.64 (Q9Z320) C29. Q9Z320 67% 50 1153 HFGAJ16 580824 177WUblastx.64 CDM protein - human pir|S44279|S44279 97% 263 403 HFIJA29839206 179 WUblastx.64 (Q9UHT1) PRO1902 PROTEIN. Q9UHT1 46% 889 806 59%1026 880 HFIJA68 847074 180 WUblastx.64 (Q9UHE8) SIX TRANSMEMBRANESTEA_HUMAN 89% 13 399 EPITHELIAL ANTIGEN OF PROSTATE. HFKES05 827572 181WUblastx.64 (BAB55088) CDNA FLJ14496 fis, BAB55088 85% 84 314 cloneNT2RM1000035. 94% 367 1722 HFKEU12 634006 182 WUblastx.64 hypotheticalprotein 3 - rat pir|S21347|S21347 52% 695 745 50% 757 933 40% 774 100754% 387 692 HFPDS07 821646 185 WUblastx.64 (O94925) GLUTAMINASE, KIDNEYGLSK_HUMAN 78% 343 513 ISOFORM, MITOCHONDRIAL 74% 2 436 PRECURS HFVGK35731868 189 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 65% 832 608PROTEIN. HFVHW43 570948 190 WUblastx.64 (Q9BGX4) HYPOTHETICAL 13.8 KDAQ9BGX4 69% 1209 1093 PROTEIN. HFXAV37 626595 191 WUblastx.64 (O60448)NEURONAL THREAD O60448 33% 583 461 PROTEIN AD7C-NTP. 68% 473 333 60%1240 1166 47% 607 539 45% 1454 1275 56% 1295 1173 59% 1287 1222 64% 607407 69% 607 461 57% 1285 1169 40% 1467 1402 48% 1321 1232 37% 558 34678% 402 361 68% 591 406 31% 549 355 60% 398 354 36% 1321 1232 41% 13641275 46% 1187 1110 47% 1453 1187 HFXBT66 580831 193 WUblastx.64 (Q9H387)PRO2550. Q9H387 73% 739 807 58% 809 907 62% 564 764 HGBER72 826710 195WUblastx.64 (Q9H387) PRO2550. Q9H387 71% 1061 969 78% 1104 1063 77% 12371103 HGBHP91 693011 198 WUblastx.64 hypothetical protein (L1H 3′region) - pir|B34087|B34087 52% 541 491 human 44% 537 34 HGCAC19 851527199 WUblastx.64 (Q9UIE9) WUGSC: H_DJ0687K01.2 Q9UIE9 34% 984 1124PROTEIN. 31% 1546 1863 96% 361 1047 24% 993 1124 22% 984 1124 40% 10021124 27% 984 1124 27% 981 1124 25% 984 1088 31% 984 1124 23% 984 112429% 984 1124 29% 984 1124 32% 1023 1124 26% 586 801 95% 2017 2712HGCAC19 801999 200 WUblastx.64 (Q9H6A1) CDNA: FLJ22454 FIS, Q9H6A1 34%984 1124 CLONE HRC09703 (FRAGMENT). 100% 184 210 31% 984 1124 29% 9841124 40% 1002 1124 27% 984 1124 29% 984 1124 27% 981 1124 21% 984 112124% 993 1124 23% 984 1124 96% 316 1056 HGCAC19 842540 201 WUblastx.64(Q9H6A1) CDNA: FLJ22454 FIS, Q9H6A1 34% 982 1122 CLONE HRC09703(FRAGMENT). 100% 182 208 31% 982 1122 29% 982 1122 40% 1000 1122 27% 9821122 29% 982 1122 27% 979 1122 21% 982 1119 24% 991 1122 23% 982 112296% 314 1045 HHEAK45 765278 202 WUblastx.64 (Q9NPB0) DJ202I21.1 (NOVELQ9NPB0 68% 1949 1458 PROTEIN) (CDNA FLJ11101 FIS, CLONE PLACE10 HHEOW19886174 204 WUblastx.64 (O18973) RAB5 GDP/GTP O18973 77% 417 623 EXCHANGEFACTOR, RABEX5. 91% 611 715 56% 166 378 92% 129 167 HHFFF87 778071 205WUblastx.64 coatomer zeta chain - bovine pir|A49465|A49465 100% 50 145HHFFL34 753230 206 WUblastx.64 (BAB55306) CDNA FLJ14793 fis, BAB55306100% 9 710 clone NT2RP4001174, w HHFFS40 824059 207 WUblastx.64 (Q9H4A6)GOLGI PROTEIN. Q9H4A6 100% 3 251 HHGDT26 658692 209 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 69% 1580 1290 CLONE COL04765. HHSBI65 801910213 WUblastx.64 (Q9H5W9) CDNA: FLJ22888 FIS, Q9H5W9 100% 270 407 CLONEKAT03934. 94% 479 1300 HHSDI53 862028 214 WUblastx.64 (Q9H387) PRO2550.Q9H387 70% 1108 935 71% 1241 1107 75% 1276 1241 HILCA24 782450 217WUblastx.64 (Q9NUU6) CDNA FLJ11127 FIS, Q9NUU6 73% 103 159 CLONEPLACE1006225. 100% 168 1169 HILCA24 869856 218 WUblastx.64 (Q9NUU6) CDNAFLJ11127 FIS, Q9NUU6 95% 104 1171 CLONE PLACE1006225. HISAT67 843549 219WUblastx.64 (Q9UH94) PROLACTIN Q9UH94 88% 219 797 REGULATORY ELEMENT-91% 788 1447 BINDING PROTEIN (PROLACTIN REGU HJBCU75 638329 220WUblastx.64 (O45030) STRABISMUS. O45030 44% 199 426 52% 464 964 HJMAA03824062 221 WUblastx.64 (Q9N032) UNNAMED PROTEIN Q9N032 71% 415 528PRODUCT. HJMAV41 862029 222 WUblastx.64 brain-specific membrane anchorpir|JC7110|JC7110 100% 14 475 protein - human HJMAY90 793678 223WUblastx.64 (Q9DC16) 1200007D18RIK Q9DC16 77% 100 312 PROTEIN (RIKENCDNA 98% 315 968 1200007D18 GENE). HJPBE39 801960 224 WUblastx.64(Q9CUS4) 4833420K19RIK Q9CUS4 33% 1 621 PROTEIN (FRAGMENT). 74% 213 1007HJPCH08 840365 226 WUblastx.64 (O95235) RABKINESIN-6 (RAB6- RB6K_HUMAN93% 9 596 INTERACTING KINESIN-LIKE PROTEI HKABU43 838573 227 WUblastx.64(AAH03633) Translocase of outer AAH03633 100% 33 62 mitochondrial membr92% 26 1597 HKACI79 853361 228 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0KDA Q9BGV8 72% 886 1104 PROTEIN. HKAFF50 790192 229 WUblastx.64 (Q9P1G7)PRO1777. Q9P1G7 99% 1753 1424 HKGBF25 738797 230 WUblastx.64 (Q9HBS7)HYPOTHETICAL 14.2 KDA Q9HBS7 71% 1708 1688 PROTEIN. 56% 1956 1708HKMLK03 734213 232 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 50% 981832 PRODUCT. 73% 856 731 HLDQU79 740755 237 WUblastx.64 (O75477) KE04P.O75477 100% 105 1142 HLDQU79 837599 3099 blastx.2 KE04P.sp|O75477|O75477 99% 81 1118 HLDRT09 830544 238 WUblastx.64 (Q9HAQ7)ATP-BINDING Q9HAQ7 86% 2 469 CASSETTE HALF-TRANSPORTER. HLHAP05 638476239 WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, Q9HA67 55% 1553 1500 CLONEMAMMA1000472. 72% 1650 1585 77% 1807 1646 HLIBO72 883431 241 WUblastx.64(AAH07829) Similar to hypothetical AAH07829 100% 65 547 protein AF140225HLICE88 840321 242 WUblastx.64 fibrinogen gamma-A chain precursorpir|A90470|FGHUG 89% 3 584 [validated] - human HLMBW89 701996 245WUblastx.64 (AAH07983) Unknown (protein for AAH07983 85% 390 247 MGC:16279). HLMGP50 647603 246 WUblastx.64 (Q9GMI7) HYPOTHETICAL 9.0 KDAQ9GMI7 61% 765 709 PROTEIN. 72% 935 807 HLQAS12 886180 249 WUblastx.64(Q9XTA8) LECTIN-LIKE Q9XTA8 71% 690 842 OXIDIZED LDL RECEPTOR. 52% 364711 HLQCL64 864966 250 HMMER PFAM: Major intrinsic protein PF00230 87.387 449 2.1.1 WUblastx.64 aquaporin 9 - human pir|JC5973|JC5973 98% 18548 HLQCX36 584786 251 WUblastx.64 (Q9UI59) PRO0478 PROTEIN. Q9UI59 87%1100 1216 HLWDB73 838453 258 WUblastx.64 (Q9H7D7) CDNA: FLJ21016 FIS,Q9H7D7 100% 660 872 CLONE CAE05735. 98% 1 657 HLYGB19 838083 261WUblastx.64 (Q9H0Q1) HYPOTHETICAL 12.3 KDA Q9H0Q1 97% 204 518 PROTEIN.HLYGY91 658703 263 WUblastx.64 (Q9H8N0) CDNA FLJ13386 FIS, Q9H8N0 94%221 391 CLONE PLACE1001104, WEAKLY SIMILAR TO MYO HMCAZ04 839783 264WUblastx.64 (Q9Y6N5) HYPOTHETICAL 50.0 KDA Q9Y6N5 100% 106 1455 PROTEIN.HMCAZ04 858210 265 WUblastx.64 (Q9Y6N5) HYPOTHETICAL 50.0 KDA Q9Y6N5100% 106 1455 PROTEIN. HMCAZ04 867910 266 WUblastx.64 (Q9Y6N5)HYPOTHETICAL 50.0 KDA Q9Y6N5 100% 106 1455 PROTEIN. HMCAZ04 887445 267WUblastx.64 (Q9Y6N5) HYPOTHETICAL 50.0 KDA Q9Y6N5 100% 107 1456 PROTEIN.HMCAZ04 668249 268 WUblastx.64 (Q9UQM8) CGI-44 PROTEIN. Q9UQM8 100% 91055 HMDAB29 584789 270 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX1772% 1186 890 CLONE KAT08285. HMEBB82 783077 272 WUblastx.64 (Q9NSE4)MITOCHONDRIAL Q9NSE4 99% 2 2206 ISOLEUCINE TRNA SYNTHETASE (FRAGMENT).HMEDE24 837027 273 WUblastx.64 (Q9BVH9) SIMILAR TO GLUCOSE Q9BVH9 94%188 1159 REGULATED PROTEIN, 58 KDA. 42% 101 742 HMEDI90 840077 274WUblastx.64 (Q9HBA3) RAB3 INTERACTING Q9HBA3 100% 81 794 PROTEIN VARIANT4 (FRAGMENT). HMELM75 587307 275 WUblastx.64 (Q9NVW5) HYPOTHETICAL 31.3KDA Q9NVW5 100% 137 391 PROTEIN. HMICP65 847403 279 WUblastx.64 (Q9HAU9)GUANINE Q9HAU9 99% 8 892 NUCLEOTIDE BINDING PROTEIN 22% 269 943 BETASUBUNIT 5L. HMSBE04 709672 281 WUblastx.64 (Q9H5V8) CDNA: FLJ22969 FIS,Q9H5V8 85% 182 3 CLONE KAT10759. HMSCL38 801919 282 WUblastx.64 (Q9P195)PRO1722. Q9P195 64% 1272 1460 72% 2918 2844 64% 2851 2759 76% 2769 2653HMSCR69 843059 283 HMMER PFAM: Zinc finger present in PF00569 48.2 113250 2.1.1 dystrophin, CBP/p300 WUblastx.64 (Q9BWK2) POTASSIUM CHANNELQ9BWK2 78% 107 1231 MODULATORY FACTOR. HMSHC86 840402 284 WUblastx.64(Q9N083) UNNAMED PORTEIN Q9N083 70% 1724 1674 PRODUCT. 67% 1674 1420HMSHU20 847410 285 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 47%1722 1453 CLONE COL04765. HMTAB77 847411 287 WUblastx.64 (P43243) MATRIN3. MAT3_HUMAN 95% 630 1385 64% 287 628 22% 2002 2175 98% 3255 3428 31%2041 2190 22% 2047 2181 23% 2584 2763 75% 2440 2760 27% 2596 2709 35%1705 1797 35% 3312 3404 91% 1384 2328 HMUAE26 747403 288 WUblastx.64(Q9P2R4) SEVEN Q9P2R4 89% 153 575 TRANSMEMBRANE DOMAIN 86% 577 1272ORPHAN RECEPTOR. HMUAN45 833072 289 WUblastx.64 (BAB55441) CDNA FLJ14993fis, BAB55441 70% 684 1238 clone Y79AA1001874, w 65% 239 955 100% 12471516 HMVBC31 825598 290 WUblastx.64 (O60725) PROTEIN-S ICMT_HUMAN 80%747 938 ISOPRENYLCYSTEINE O- 87% 121 789 METHYLTRANSFERASE (E HMVDU15801969 291 WUblastx.64 (Q9BTJ2) SIMILAR TO CGI-30 Q9BTJ2 100% 75 917PROTEIN. HMWBL03 822861 292 WUblastx.64 (Q9BWT1) C-MYC TARGET JP1.Q9BWT1 85% 137 1240 HMWJF53 758158 293 WUblastx.64 (Q9GZU7) NUCLEAR LIMQ9GZU7 91% 3 170 INTERACTOR-INTERACTING 100% 154 720 FACTOR. HNEAK81722235 294 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 56% 770 1087PRODUCT. HNECL22 799541 295 WUblastx.64 (Q9P0J2) MITOCHONDRIAL Q9P0J294% 1771 2331 SOLUTE CARRIER. HNEDH88 815675 297 WUblastx.64 (Q9GML5)HYPOTHETICAL 8.0 KDA Q9GML5 56% 1706 1849 PROTEIN. HNFAC50 815676 298WUblastx.64 (Q9H286) SEROLOGICALLY Q9H286 100% 425 282 DEFINED BREASTCANCER ANTIGEN NY-BR-20 (FRAGME HNFHF34 722237 300 WUblastx.64 (Q9NZX0)HSPC068. Q9NZX0 100% 9 431 34% 9 404 35% 3 407 33% 9 407 32% 129 422HNGAK51 603910 301 WUblastx.64 (O60448) NEURONAL THREAD O60448 61% 563601 PROTEIN AD7C-NTP. 67% 733 915 65% 702 878 74% 714 914 HNGAM58 688114302 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 71% 1020 1061 CLONECOL04765. 85% 1081 1143 53% 818 1003 HNGGP65 597449 310 WUblastx.64(Q9GMU5) HYPOTHETICAL 14.1 KDA Q9GMU5 31% 69 302 PROTEIN. 47% 398 541HNGJB41 852178 313 WUblastx.64 probable oxysterol-binding proteinpir|T02435|T02435 100% 128 9 DJ430N08.1 - human (fragment) HNHFE71834487 320 WUblastx.64 hypothetical protein pir|T47135|T47135 67% 822583 DKFZp761L0812.1 - human (fragment) HNHGK22 597451 321 WUblastx.64hypothetical protein (L1H 3′ region) - pir|B34087|B34087 41% 483 37human 41% 333 10 50% 733 485 HNHHB10 634589 322 WUblastx.64 (Q9BVD9)UNKNOWN (PROTEIN Q9BVD9 70% 658 608 FOR MGC: 5149). 73% 845 711 73% 717661 HNTBT17 855957 324 WUblastx.64 (Q9NZF3) BM-001. Q9NZF3 45% 818 134261% 729 947 84% 556 774 HOACG07 792928 328 WUblastx.64 (Q9GZN8)DJ1009E24.3 (A NOVEL Q9GZN8 99% 183 704 PROTEIN) (CDNA FLJ14158 FIS,CLONE NT2R HODBV05 825283 331 WUblastx.64 (Q13878) 94 KDA B-RAF PROTEINQ13878 100% 566 661 (FRAGMENT). HODCZ32 836069 332 WUblastx.64 (Q9NSI6)WD-REPEAT PROTEIN 9 WDR9_HUMAN 86% 8 331 (FRAGMENT). HOEBK60 789396 333WUblastx.64 (Q9H916) CDNA FLJ13081 FIS, Q9H916 98% 132 1916 CLONENT2RP3002033. 100% 14 109 88% 106 159 HOFAA78 836646 334 WUblastx.64(Q9NXS2) CDNA FLJ20084 FIS, Q9NXS2 90% 529 792 CLONE COL03526. 50% 9 8088% 29 529 HOFNB74 762821 335 WUblastx.64 (Q99JH1) HYPOTHETICAL 17.7 KDAQ99JH1 72% 44 187 PROTEIN. 97% 199 471 HORBV76 839270 339 WUblastx.64(Q9Y2B2) Q9Y2B2 91% 30 761 PHOSPHATIDYLINOSITOL GLYCAN, CLASS L (EC3.5.—.—) (PIG-L PRO HOSDO75 862049 340 WUblastx.64 (Q9D099)1110057L18RIK Q9D099 89% 11 202 PROTEIN. 88% 259 630 HOSEC25 688055 341WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 73% 530 631 PROTEIN.65% 627 809 64% 1501 1451 56% 1440 1222 HOSEJ94 795132 343 WUblastx.64(Q9GZY3) HT032 (PRK1- Q9GZY3 92% 363 986 ASSOCIATED PROTEIN AWP1)(PROTEIN ASSOCIATED WIT HOUCA21 655359 344 WUblastx.64 (Q9HBS7)HYPOTHETICAL 14.2 KDA Q9HBS7 78% 988 1110 PROTEIN. HOUDE92 580866 345WUblastx.64 (Q9HBT2) HYPOTHETICAL 17.2 KDA Q9HBT2 96% 21 245 PROTEIN.HOUDR07 745404 346 WUblastx.64 (Q9HBV4) ANGIOPOIETIN-LIKE Q9HBV4 87% 1701384 PROTEIN PP1158. HOUED72 858547 347 WUblastx.64 (Q9CRP8) RIBOSOMALPROTEIN Q9CRP8 84% 676 774 L15 (FRAGMENT). 85% 110 682 HOUFS04 771564348 WUblastx.64 (Q9VN45) CG12001 PROTEIN. Q9VN45 32% 1362 1982 39% 9151106 26% 141 380 HOUHI25 888279 349 WUblastx.64 (O95003) WUGSC:H_DJ0593H12.2 O95003 94% 73 783 PROTEIN. HPCAL26 762822 352 WUblastx.64(O95084) SERINE PROTEASE O95084 98% 398 640 (HYPOTHETICAL 43.0 KDA 76%135 497 PROTEIN) (PROTEASE, S HPFBA54 635539 354 WUblastx.64 (Q9HBW6)NAG13. Q9HBW6 76% 795 733 73% 766 602 84% 602 393 86% 135 91 79% 394 128HPFCI36 855966 355 WUblastx.64 (Q9NX47) CDNA FLJ20445 FIS, Q9NX47 100% 9320 CLONE KAT05170. HPJBU43 862058 360 WUblastx.64 (Q9P1E1) PRO2221.Q9P1E1 54% 187 44 HPMCJ84 562779 363 WUblastx.64 (Q9NX85) CDNA FLJ20378FIS, Q9NX85 74% 619 479 CLONE KAIA0536. 69% 759 613 HPMCV30 612870 364WUblastx.64 (Q9BVD9) UNKNOWN (PROTEIN Q9BVD9 76% 384 334 FOR MGC: 5149).68% 590 399 HPQAX38 843592 366 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0KDA Q9BGV8 74% 664 768 PROTEIN. 68% 543 674 HPQAX38 845752 367WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 74% 664 768 PROTEIN.68% 543 674 HPRBH85 695752 370 WUblastx.64 (BAB55300) CDNA FLJ14784 fis,BAB55300 62% 2 616 clone NT2RP4000713. 86% 534 1085 HPRCA64 824074 371WUblastx.64 (P55161) NCK-ASSOCIATED NCP1_RAT 100% 1021 1926 PROTEIN 1(NAP 1) (P125NAP1) 85% 387 1019 (MEMBR 93% 11 481 HPRCD35 853551 372WUblastx.64 hypothetical protein pir|T50629|T50629 100% 320 613DKFZp762L1710.1 - human 57% 2 499 (fragment) HPTRM02 812879 373WUblastx.64 (Q9UJU6) SRC HOMOLOGY 3 Q9UJU6 92% 332 940 DOMAIN-CONTAININGPROTEIN 97% 2 106 HIP-55 (DREBRIN F). 96% 98 190 HRAAD30 866187 376WUblastx.64 (Q9H6V0) CDNA: FLJ21839 FIS, Q9H6V0 89% 23 1393 CLONEHEP01794. HRADA42 827302 377 WUblastx.64 hypothetical protein C11D2.4 -pir|T32961|T32961 48% 387 668 Caenorhabditis elegans 74% 668 931 HRADF49866481 378 WUblastx.64 (Q9H6L1) CDNA: FLJ22169 FIS, Q9H6L1 90% 13 825CLONE HRC00632. 84% 813 1379 75% 1291 1593 34% 1590 1685 HRADN25 800628379 WUblastx.64 (Q9HB07) MYG1 PROTEIN. MYG1_HUMAN 96% 47 1174 HRDAI17560720 381 WUblastx.64 (Q9NUM6) CDNA FLJ11267 FIS, Q9NUM6 59% 1305 1475CLONE PLACE1009174. HRDDQ39 840405 382 WUblastx.64 (Q9NX85) CDNAFLJ20378 FIS, Q9NX85 53% 582 436 CLONE KAIA0536. 65% 775 578 HRDER22688056 383 WUblastx.64 (Q9NW07) CDNA FLJ10390 FIS, Q9NW07 80% 9 248CLONE NT2RM4000104, 100% 357 431 MODERATELY SIMILAR TO 39% 120 227 28%15 203 38% 254 316 HRDEX93 816046 384 WUblastx.64 (Q9UBV8) PEFLIN.Q9UBV8 100% 313 864 HRDFK37 840381 385 WUblastx.64 (Q9P195) PRO1722.Q9P195 69% 536 652 40% 50 115 HRGBD54 828436 386 WUblastx.64 (O95819)HPK/GCK-LIKE KINASE O95819 51% 32 253 HGK. 74% 253 645 27% 6 149 92% 7812019 HSAVA08 580870 388 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDAQ9BGW3 57% 949 896 PROTEIN. 42% 926 792 63% 796 764 66% 1059 934 HSAWZ40634000 391 WUblastx.64 (O00549) ORF2-LIKE PROTEIN O00549 64% 951 610(FRAGMENT). 60% 613 8 HSDZM54 637870 393 WUblastx.64 NADH dehydrogenase(ubiquinone) pir|A00422|DNHUN3 88% 226 360 (EC 1.6.5.3) chain 3 - humanmitochondrion HSHBF76 715838 394 WUblastx.64 (AAH08335) Unknown (proteinfor AAH08335 86% 762 457 IMAGE: 3506202) (Fra 73% 882 748 100% 1267 836HSJBY32 702020 396 WUblastx.64 (Q9GZZ6) NEURONAL NICOTINIC Q9GZZ6 81%466 639 ACETYLCHOLINE ALPHA10 57% 215 514 SUBUNIT PRECURSOR ( HSLHX15777861 399 WUblastx.64 catalase (EC 1.11.1.6) - pir|I40767|I40767 86%162 76 Campylobacter jejuni HSNBM34 635131 402 WUblastx.64 acyl-CoAdehydrogenase (EC 1.3.99.—) pir|S54183|S54183 84% 1548 1979very-long-chain specific - human 100% 251 1546 HSOAH16 827058 403WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 57% 682 623 CLONEKAIA0536. 81% 624 544 68% 524 384 HSQDO85 853393 405 WUblastx.64(Q9VCK0) CG10161 PROTEIN. Q9VCK0 67% 485 988 60% 60 521 56% 10 57HSQES57 831222 406 WUblastx.64 (Q96EW4) Unknown (protein for Q96EW4 94%195 980 MGC: 19936). HSRBE06 871264 407 WUblastx.64 (Q9H387) PRO2550.Q9H387 70% 1608 1327 HSSDI26 560722 408 WUblastx.64 (Q9BVD9) UNKNOWN(PROTEIN Q9BVD9 68% 1398 1264 FOR MGC: 5149). HSSEA64 853395 409WUblastx.64 (Q9HBT2) HYPOTHETICAL 17.2 KDA Q9HBT2 98% 7 243 PROTEIN.HSSEF77 658725 410 WUblastx.64 (O95637) WW DOMAIN BINDING O95637 42% 10246 PROTEIN-1. 83% 296 829 HSSFE38 742512 411 HMMER PFAM: RibonucleaseHII PF01351 76.3 184 −142 2.1.1 WUblastx.64 (O75792) RIBONUCLEASE HIRNHL_HUMAN 91% 156 635 LARGE SUBUNIT (EC 3.1.26.—) 99% 587 1051 (RNASEHSWBE76 751308 413 WUblastx.64 (Q9NW15) CDNA FLJ10375 FIS, Q9NW15 100%126 266 CLONE NT2RM2001950. HSXCP38 895392 414 WUblastx.64hydroxymethylglutaryl-CoA lyase (EC pir|B45470|B45470 70% 17 8954.1.3.4) - chicken HSYBI06 740766 415 WUblastx.64 (Q9BGV8) HYPOTHETICAL10.0 KDA Q9BGV8 69% 916 954 PROTEIN. 78% 821 913 HT5GR59 801930 420WUblastx.64 (O60496) DOCKING PROTEIN. O60496 72% 70 1284 HTAEI78 637684421 WUblastx.64 (Q9UKQ2) ADAM 28 PRECURSOR AD28_HUMAN 90% 85 174 (EC3.4.24.—) (A DISINTEGRIN AND HTDAA78 566861 422 WUblastx.64 (Q9D8E7)5830443F10RIK Q9D8E7 58% 84 302 PROTEIN. HTEAG62 812332 423 WUblastx.64(Q9Y5Z7) HOST CELL FACTOR 2. Q9Y5Z7 60% 1 57 93% 14 2011 30% 107 631HTECB02 806305 424 WUblastx.64 (AAK39520) BTB domain protein AAK3952095% 33 1211 (Fragment). HTECC15 866488 425 WUblastx.64 (Q92558)WISKOTT-ALDRICH WAS1_HUMAN 95% 321 1100 SYNDROME PROTEIN FAMILY 70% 15251998 MEMBER 1 ( 89% 1105 1281 HTEDS12 838621 428 WUblastx.64 (Q9H0K0)HYPOTHETICAL 81.8 KDA Q9H0K0 97% 1029 1391 PROTEIN. 42% 1269 1490 100%16 1011 HTEEF26 789606 431 WUblastx.64 (Q9H7X7) CDNA FLJ14117 FIS,Q9H7X7 81% 80 634 CLONE MAMMA1001785. HTEEF26 879704 432 WUblastx.64(Q9H7X7) CDNA FLJ14117 FIS, Q9H7X7 81% 80 634 CLONE MAMMA1001785.HTEEW69 764835 433 WUblastx.64 (Q9Z1H7) GSG1. Q9Z1H7 65% 850 927 85% 707769 50% 519 662 66% 908 943 65% 182 544 HTEGS07 827700 434 WUblastx.64(Q9D143) 1110030K22RIK Q9D143 96% 183 593 PROTEIN. HTEHA56 806461 436WUblastx.64 (Q9H9A0) CDNA FLJ12895 FIS, Q9H9A0 94% 2 217 CLONENT2RP2004187, WEAKLY 65% 70 468 SIMILAR TO ZIN HTEJD29 695798 438WUblastx.64 (Q60713) REVERSE Q60713 42% 1115 1285 TRANSCRIPTASE. 47% 8741089 HTEMQ17 840387 440 WUblastx.64 (Q9D4P8) 4930579G24RIK Q9D4P8 90%120 359 PROTEIN. HTENR63 877952 441 WUblastx.64 (Q9HD71) HYPOTHETICALQ9HD71 33% 1278 1358 NUCLEAR FACTOR SBBI22. 78% 26 1168 HTGGM44 842856442 WUblastx.64 probable phosphodiesterase I (EC pir|T43461|T43461 100%1400 1924 3.1.4.1) - human (fragment) 83% 1925 2488 HTLBT80 840045 445WUblastx.64 (Q9NQQ7) BA394O2.1 (CGI-15 Q9NQQ7 76% 1214 1405 PROTEIN).74% 804 1223 47% 780 845 78% 313 825 HTLDA84 686397 446 WUblastx.64(Q9H387) PRO2550. Q9H387 79% 1265 1134 60% 1442 1398 65% 1398 1243HTLDN29 790195 447 WUblastx.64 (Q9CWL8) 5730471K09RIK Q9CWL8 96% 15 1226PROTEIN. HTLEC82 811992 449 WUblastx.64 (Q99MI0) CELL GROWTH Q99MI0 98%111 455 REGULATOR FALKOR. HTLEM16 779133 450 WUblastx.64 (O95638) WWDOMAIN BINDING O95638 92% 50 541 PROTEIN-2. 28% 987 1142 48% 617 841HTLEV48 723799 451 WUblastx.64 (BAB55550) Bk125H2.1 protein. BAB5555094% 10 825 HTLFA13 535937 452 WUblastx.64 (Q9UHT1) PRO1902 PROTEIN.Q9UHT1 57% 1118 873 HTLGI89 835069 454 WUblastx.64 (Q9BXS5) CLATHRIN-Q9BXS5 98% 104 682 ASSOCIATED PROTEIN AP47. 99% 675 1370 HTLIF11 843506455 WUblastx.64 (Q9I8S4) ORNITHINE Q9I8S4 68% 309 356 DECARBOXYLASE-2.59% 353 1687 HTLIF12 834946 456 WUblastx.64 (Q9DAR1) 1700001K04RIKQ9DAR1 47% 291 752 PROTEIN. HTLIF12 842691 457 WUblastx.64 (Q9DAR1)1700001K04RIK Q9DAR1 47% 293 754 PROTEIN. HTLIF12 870167 458 WUblastx.64(Q9DAR1) 1700001K04RIK Q9DAR1 47% 293 754 PROTEIN. HTLIF12 886780 459WUblastx.64 (Q9DAR1) 1700001K04RIK Q9DAR1 47% 293 754 PROTEIN. HTLIF12891533 460 WUblastx.64 (Q9DAR1) 1700001K04RIK Q9DAR1 47% 293 754PROTEIN. HTLIF12 901225 461 WUblastx.64 (Q9DAR1) 1700001K04RIK Q9DAR147% 293 754 PROTEIN. HTNBK13 831967 463 WUblastx.64 (Q9Y3M2)HYPOTHETICAL 14.5 KDA Q9Y3M2 81% 123 500 PROTEIN. HTOAM11 664508 465WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, Q9H5R3 77% 428 363 CLONELNG09295. 75% 586 425 HTOEV16 853616 468 WUblastx.64 (Q9NRZ5) 1-ACYL-SN-PLCD_HUMAN 98% 201 383 GLYCEROL-3-PHOSPHATE 95% 379 1164 ACYLTRANSFERASEDEL HTOHO21 732808 470 WUblastx.64 P47 LBC oncogene - humanpir|I38434|I38434 97% 581 438 HTOHQ05 853621 471 WUblastx.64 (Q9UII4)CYCLIN-E BINDING Q9UII4 100% 669 791 PROTEIN 1. HTOJL95 806212 472WUblastx.64 (Q15605) ORF1 CODES FOR A 40 KDA Q15605 86% 192 61 PRODUCT.57% 876 730 57% 751 161 HTOJL95 762851 473 WUblastx.64 (Q15401) LINE-1REPEAT MRNA Q15401 36% 683 609 WITH 2 OPEN READING FRAMES. 59% 966 82071% 607 248 HTPDU17 840596 474 WUblastx.64 (Q9NW00) CDNA FLJ10404 FIS,Q9NW00 80% 553 1308 CLONE NT2RM4000486. 64% 1143 1664 HTSFJ32 637720 475WUblastx.64 (Q9WUW2) VESICLE Q9WUW2 64% 747 788 ASSOCIATED MEMBRANE 94%448 609 PROTEIN 2B. HTTCB60 853401 476 WUblastx.64 (Q9HAW0) RNAPOLYMERASE III Q9HAW0 90% 6 881 TRANSCRIPTION INITIATION FACTOR BRFU.HTTEE41 840950 477 WUblastx.64 (P78371) T-COMPLEX PROTEIN 1, TCPB_HUMAN98% 92 1696 BETA SUBUNIT (TCP-1-BETA) (CC HTTEZ02 702027 478 WUblastx.64(Q9UEZ7) MAKORIN 1. Q9UEZ7 56% 278 346 98% 6 272 HTWEH94 561680 479WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 60% 1150 929 PROTEIN.HTXDC38 801935 482 WUblastx.64 (Q9BTX3) SIMILAR TO HSPC171 Q9BTX3 99%100 573 PROTEIN. HTXDC77 844258 483 HMMER PFAM: Class IHistocompatibility PF00129 103.3 137 259 2.1.1 antigen, domains alpha 1and 2 WUblastx.64 (P03989) HLA CLASS I 1B14_HUMAN 63% 880 945HISTOCOMPATIBILITY ANTIGEN, 71% 65 256 B-27 ALPHA 80% 282 863 HTXFA72853410 487 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 59% 1688 1557PRODUCT. 66% 1839 1681 HTXKF95 834438 489 WUblastx.64 (AAH08360) Similarto hypothetical AAH08360 85% 233 553 protein FLJ22376 100% 2 112 HTXMZ07834881 490 WUblastx.64 (Q9BRF3) SIMILAR TO RIKEN Q9BRF3 90% 3 1469 CDNA2810468K17 GENE. HUFCL31 801938 491 WUblastx.64 (Q9D311) 9030623N16RIKQ9D311 60% 280 1224 PROTEIN. HUKBT67 844446 492 WUblastx.64 (BAB55428)CDNA FLJ14975 fis, BAB55428 100% 1040 1216 clone THYRO1001405, w 100% 861 30% 80 241 HUKDY82 570896 494 WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS,Q9HA67 59% 1405 1145 CLONE MAMMA1000472. HUSCJ14 894699 495 WUblastx.64tex261 protein - mouse pir|S47481|S47481 99% 74 661 HUSGL67 792637 496WUblastx.64 (Q9Y2G2) CARD DOMAIN CRD8_HUMAN 100% 347 421 PROTEIN 8(APOPTOTIC PROTEIN 65% 947 1006 NDPP1) (D 97% 469 954 HUSGU40 684975 497WUblastx.64 (Q9BX98) UBIQUITIN A-52 Q9BX98 75% 840 433 RESIDUE RIBOSOMALPROTEIN FUSION PRODUCT 1 (F HUVDJ48 564853 499 WUblastx.64 SHORT ISOFORMOF Q9P2N4 sp_vs|Q9P2N4- 92% 1510 1668 01|Q9P2N4 HWAAI12 830432 500WUblastx.64 (Q9BWW4) SINGLE STRANDED Q9BWW4 82% 512 829 DNA BINDINGPROTEIN-1. 87% 92 394 69% 941 1252 36% 521 685 37% 752 826 HWBCN36722259 502 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 69% 1007900 PROTEIN. 57% 887 846 HWBDJ08 762860 503 WUblastx.64 probable polpolyprotein-related pir|S21348|S21348 47% 901 833 protein 4 - rat 43%1262 1131 53% 1134 904 HWDAC26 821335 505 WUblastx.64 (Q14287)HYPOTHETICAL Q14287 51% 1316 1471 PROTEIN (FRAGMENT). 57% 1093 1323HWDAG96 796743 506 WUblastx.64 (AAH01119) Integrin beta 4 bindingAAH01119 100% 108 842 protein. HWHPB78 740778 508 WUblastx.64 (Q9BUK4)SIMILAR TO Q9BUK4 61% 360 614 HYPOTHETICAL PROTEIN 100% 677 817FLJ10709. HYABC84 789854 509 WUblastx.64 (Q99L03) SIMILAR TO TRP4-Q99L03 89% 209 553 ASSOCIATED PROTEIN TAP1 (FRAGMENT). HYABC84 865064510 WUblastx.64 (Q9H429) DJ756N5.2 (A NOVEL Q9H429 92% 163 618 PROTEIN(DKFZP727M231) SIMILAR TO TRP4-AS H2CBD20 570796 511 WUblastx.64(Q14288) HYPOTHETICAL Q14288 42% 758 988 PROTEIN (FRAGMENT). 51% 9871223 H2CBH91 826669 512 WUblastx.64 (Q9NXA3) CDNA FLJ20357 FIS, Q9NXA363% 133 222 CLONE HEP16545. 53% 3 125 75% 603 737 68% 263 643 H2LBA54684290 513 WUblastx.64 (O60875) APOPTOSIS SPECIFIC O60875 97% 172 996PROTEIN (DJ134E15.2) (APOPTOSIS SPECIFIC H2LBB09 658667 514 WUblastx.64(Q9P0R6) HSPC210. Q9P0R6 95% 465 536 97% 73 477 H2LBB09 830636 515WUblastx.64 (Q9P0R6) HSPC210. Q9P0R6 100% 504 575 97% 112 516 H2MBF60695714 518 WUblastx.64 transcription factor TFIID 32K chainpir|I39141|I39141 100% 163 909 TAFII32 - human H6EEA48 847111 520WUblastx.64 (AAH07644) Similar to RIKEN cDNA AAH07644 90% 478 9339430029K10 gene (F 96% 27 482 H6EEN71 829201 521 WUblastx.64 (Q9BW90)SIMILAR TO Q9BW90 100% 1943 1779 PEROXISOME BIOGENESIS FACTOR 10.H6EEO05 865424 522 HMMER PFAM: EF hand PF00036 25 328 414 2.1.1WUblastx.64 hypothetical protein pir|T17225|T17225 97% 265 522DKFZp564C246.1 - human HACBJ11 797625 528 WUblastx.64 band-6-protein -human pir|S60712|S60712 100% 8 139 HACBS86 603946 529 WUblastx.64(Q9BQB1) HYPOTHETICAL 22.5 KDA Q9BQB1 66% 89 682 PROTEIN. HADCL19 599065535 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 57% 1070 780 CLONECOL04765. HADDC04 601695 537 WUblastx.64 (Q9GML5) HYPOTHETICAL 8.0 KDAQ9GML5 57% 2522 2379 PROTEIN. HADDP51 853356 539 HMMER PFAM: TBC domainPF00566 52.3 357 509 2.1.1 WUblastx.64 (Q9H695) CDNA: FLJ22474 FIS,Q9H695 99% 12 701 CLONE HRC10568. HADET62 607615 541 WUblastx.64retrovirus-related hypothetical protein pir|S23650|S23650 33% 506 330II - human 1 27% 325 77 50% 657 592 44% 808 668 HADEY08 799507 542WUblastx.64 (Q9NX94) CDNA FLJ20367 FIS, Q9NX94 98% 663 1076 CLONEHEP18101. HADEY22 861628 544 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS,Q9H728 77% 590 459 CLONE COL04765. HADFB84 668229 545 WUblastx.64(Q9H387) PRO2550. Q9H387 67% 758 1009 HADFD10 843934 547 WUblastx.64(Q9P1C6) PRO2738. Q9P1C6 52% 1254 1054 HADFW20 599066 550 WUblastx.64(Q9H9H0) CDNA FLJ12759 FIS, Q9H9H0 83% 1065 823 CLONE NT2RP2001347.HADFX10 741054 551 WUblastx.64 (O60448) NEURONAL THREAD O60448 45% 12251040 PROTEIN AD7C-NTP. 62% 726 646 35% 1221 808 39% 1194 850 56% 917 72933% 965 729 57% 1022 939 45% 726 628 51% 972 772 59% 972 715 57% 12251169 34% 1188 940 HADFY80 654831 552 WUblastx.64 (Q9H8X9) CDNA FLJ13153FIS, Q9H8X9 94% 2 169 CLONE NT2RP3003409, WEAKLY SIMILAR TO HUM HADXA10772423 555 WUblastx.64 (Q9NZ51) NEUROENDOCRINE Q9NZ51 78% 132 311DIFFERENTIATION FACTOR. 79% 295 798 HADXA10 859777 556 WUblastx.64(Q9D792) 9130011K15RIK Q9D792 49% 173 472 PROTEIN. HAFBB15 608180 557HMMER PFAM: RNA 3′-terminal phosphate PF01137 159.5 186 440 2.1.1cyclase WUblastx.64 RNA-3′-phosphate cyclase (EC pir|T48844|T48844 93% 6446 6.5.1.4) 1 [validated] - human HAGAB62 588471 559 WUblastx.64(Q9H2I4) DC42. Q9H2I4 77% 8 232 HAGAB83 823044 560 WUblastx.64 (Q9NX17)CDNA FLJ20489 FIS, Q9NX17 47% 1597 1472 CLONE KAT08285. 76% 1817 1599HAGAF75 561933 562 WUblastx.64 (Q9UI59) PRO0478 PROTEIN. Q9UI59 77% 12031310 HAGAK40 731929 563 WUblastx.64 (Q9H387) PRO2550. Q9H387 80% 506 65870% 707 838 HAGAZ36 564230 565 WUblastx.64 pro-pol-dUTPase polyprotein -murine pir|T29097|T29097 66% 613 578 endogenous retrovirus ERV-L 38% 897655 (fragment) 34% 572 27 HAGBL31 679582 567 WUblastx.64 (Q13416) ORIGINRECOGNITION ORC2_HUMAN 97% 509 610 COMPLEX SUBUNIT 2. HAGBO09 853357 568WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 78% 1533 1249 CLONEKAT08285. HAGBO12 601431 569 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDAQ9BGW3 63% 348 241 PROTEIN. 76% 532 353 HAGBS89 846292 571 WUblastx.64(Q9P195) PRO1722. Q9P195 56% 1125 841 HAGBV06 701966 572 WUblastx.64(Q9UHC7) MAKORIN 1. Q9UHC7 66% 28 195 HAGBV25 838174 573 WUblastx.64(Q9H7C8) CDNA: FLJ21040 FIS, Q9H7C8 99% 1 1644 CLONE CAE10642. HAGBV29837203 574 WUblastx.64 (Q9H387) PRO2550. Q9H387 70% 2054 1761 71% 439585 60% 309 455 56% 749 955 48% 732 836 73% 687 731 HAGCC87 638587 575WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 65% 992 1105 PROTEIN.36% 54 116 57% 801 980 HAGCI69 560596 577 WUblastx.64 (Q9UI59) PRO0478PROTEIN. Q9UI59 51% 1015 1185 HAGCZ70 747697 579 WUblastx.64 (Q9H397)PRO2852. Q9H397 41% 1672 1544 75% 1490 1359 77% 1366 1235 HAGDC73 724860580 WUblastx.64 (Q9V662) CG12367 PROTEIN. Q9V662 37% 536 1006 HAGDJ53821315 584 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 70% 18731781 PROTEIN. 46% 1796 1713 41% 1782 1582 HAGDL51 637488 586 WUblastx.64(O60448) NEURONAL THREAD O60448 61% 1639 1532 PROTEIN AD7C-NTP. 70% 1103 HAGDO70 812393 587 WUblastx.64 platelet-activating factorpir|JC4246|JC4246 94% 185 877 acetylhydrolase (EC 3.1.1.—) gamma chain -human HAGDT30 589514 588 WUblastx.64 (O75592) PROTEIN ASSOCIATED O75592100% 11 280 WITH MYC. 24% 11 208 100% 1125 1946 25% 295 933 90% 511 113145% 1445 1504 HAGDW68 835631 589 WUblastx.64 (AAC14670) AAC14670 100%390 470 WUGSC: H_DJ0651K02.1 protein 99% 2 385 (Fragment). HAGEK86748222 592 WUblastx.64 (O43237) DYNEIN LIGHT DYJ2_HUMAN 88% 1066 1617INTERMEDIATE CHAIN 2, CYTOSOLIC (LIC5 HAGEP30 604478 593 WUblastx.64(Q9H387) PRO2550. Q9H387 84% 594 517 67% 788 606 HAGEQ67 838445 595WUblastx.64 (Q94532) PUTATIVE TYPE III Q94532 55% 22 123 ALCOHOLDEHYDROGENASE. 59% 108 722 HAGEU26 608183 596 WUblastx.64 (Q9GMX5)HYPOTHETICAL 12.9 KDA Q9GMX5 59% 356 481 PROTEIN. HAGFM58 604536 603WUblastx.64 (Q9H3C0) PRO0898. Q9H3C0 62% 10 144 HAGFT48 780112 604WUblastx.64 (Q9Y2Y7) FOOCEN-M (NOGO-B Q9Y2Y7 80% 761 1090 PROTEIN)(RTN-XS) (RETICULON 100% 1156 1281 4B). 48% 233 559 HAGFU31 751713 605WUblastx.64 (O60448) NEURONAL THREAD O60448 65% 1214 1083 PROTEINAD7C-NTP. 68% 1245 1084 45% 1093 1028 52% 1015 953 68% 1094 1029 71%1230 967 HAGFW13 634611 606 WUblastx.64 (O00549) ORF2-LIKE PROTEINO00549 65% 398 321 (FRAGMENT). 65% 453 385 70% 307 164 HAGHE85 838059607 WUblastx.64 (Q9P195) PRO1722. Q9P195 58% 1665 1498 69% 1511 1365HAHSD51 847014 612 WUblastx.64 (Q9D8B4) 2010012C24RIK Q9D8B4 50% 99 176PROTEIN. 61% 182 505 HAIBV91 852223 615 WUblastx.64 (Q9N083) UNNAMEDPORTEIN Q9N083 59% 672 899 PRODUCT. 40% 1911 1955 HAICE62 834523 616WUblastx.64 (Q9H3T5) MOB1 PROTEIN Q9H3T5 100% 203 850 (HYPOTHETICAL 25.1KDA PROTEIN). HAICL90 637491 617 WUblastx.64 (Q9N083) UNNAMED PORTEINQ9N083 63% 716 438 PRODUCT. HAIDP45 847015 619 WUblastx.64 (AAH08590)Hypothetical 47.9 kDa AAH08590 100% 986 1096 protein. HAJAB88 780114 620HMMER PFAM: Ribosomal protein L34 PF00468 32.3 276 401 2.1.1 WUblastx.64(Q9BQ48) MITOCHONDRIAL Q9BQ48 98% 126 374 RIBOSOMAL PROTEIN L34 (L34MT)(UNKNOWN) (PROTE HAMGG01 783864 624 WUblastx.64 (Q9BY78) RING FINGERPROTEIN Q9BY78 86% 7 342 WITH LEUCINE ZIPPER RNF26. HANKC93 847018 626WUblastx.64 (Q9H387) PRO2550. Q9H387 67% 648 565 52% 876 820 61% 748 656HAPAD35 840584 627 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 76%1346 1245 CLONE KAIA0536. 63% 1237 1064 HAPBR13 609976 628 WUblastx.64(Q9H6T0) CDNA: FLJ21918 FIS, Q9H6T0 26% 273 452 CLONE HEP04006. 51% 95274 40% 424 762 HAPBU09 762803 629 WUblastx.64 (O60859) NEUROPATHYTARGET O60859 100% 3 545 ESTERASE. HAPNJ33 835554 632 WUblastx.64(BAA85159) Sec61. BAA85159 100% 1200 1403 98% 163 1230 HAPNL62 790340633 WUblastx.64 (BAB55063) CDNA FLJ14456 fis, BAB55063 93% 1 1977 cloneHEMBB1001915, m HAPNO50 834384 634 WUblastx.64 hypothetical proteinpir|T08701|T08701 98% 27 332 DKFZp564N123.1 - human (fragment) 88% 3 2986% 323 883 HAPPW83 847020 636 WUblastx.64 (Q9H387) PRO2550. Q9H387 77%626 757 84% 475 627 HAPRK55 735887 643 WUblastx.64 (Q9NX17) CDNAFLJ20489 FIS, Q9NX17 63% 1379 1068 CLONE KAT08285. HAPSH37 847021 644WUblastx.64 (Q9H387) PRO2550. Q9H387 75% 63 28 84% 199 68 HAQBY85 832384646 WUblastx.64 (Q9D4H9) 4932409F11RIK Q9D4H9 100% 17 358 PROTEIN. 55%1663 1716 28% 1066 1212 34% 1459 1728 93% 361 1539 HAQBZ15 801966 647WUblastx.64 (AAH07201) Unknown (protein for AAH07201 100% 6 86 IMAGE:2961284) (Fra 30% 1717 1824 93% 175 711 37% 1019 1564 29% 1277 1510 35%1711 1836 97% 1705 1956 35% 843 953 31% 205 357 27% 187 408 67% 641 170852% 1711 1836 31% 849 962 31% 1078 1296 26% 1241 1696 36% 1123 1266 30%1292 1564 27% 1081 1146 37% 882 953 30% 205 498 29% 1684 1938 29% 196357 27% 1054 1317 90% 83 181 HARAE26 560598 650 WUblastx.64 (Q9H743)CDNA: FLJ21394 FIS, Q9H743 65% 1204 1076 CLONE COL03536. 75% 1068 925HARAT69 769389 651 WUblastx.64 (Q9VZ55) CG1582 PROTEIN. Q9VZ55 48% 21360 HARAZ81 832380 652 WUblastx.64 (Q9BQ36) MITOCHONDRIAL Q9BQ36 97% 7327 RIBOSOMAL PROTEIN BMRP64 (HYPOTHETICAL 15.1 KD HASAU26 845848 653WUblastx.64 (Q9H964) CDNA FLJ12984 FIS, Q9H964 94% 3 107 CLONENT2RP3000047, WEAKLY 95% 132 194 SIMILAR TO NPL 98% 820 1425 40% 24052479 98% 188 829 100% 98 133 HASAY07 834511 655 WUblastx.64 catalase (EC1.11.1.6) - pir|I40767|I40767 96% 263 177 Campylobacter jejuni HATAE01654834 656 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 71% 569 507CLONE KAT08285. 95% 636 574 72% 790 647 HATAL05 847023 658 WUblastx.64(Q9ER61) MDM2 BINDING Q9ER61 68% 10 876 PROTEIN. HATCF80 780460 661WUblastx.64 (Q99LV8) UNKNOWN (PROTEIN Q99LV8 78% 9 479 FOR IMAGE:3489486) (FRAGMENT). HATCI67 847024 662 WUblastx.64 (Q9UHU3) PRO1659.Q9UHU3 85% 214 528 HATDH23 603959 668 WUblastx.64 (O43439) MTG8-LIKEPROTEIN O43439 98% 1 348 (MTG8 RELATED PROTEIN) (EHT) (EHT PROTEIN)HATDO84 609850 670 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 58%798 646 CLONE KAIA0536. 77% 919 812 HATDU01 847028 671 WUblastx.64(Q9H387) PRO2550. Q9H387 81% 1257 1225 58% 1198 974 HAUCC84 830672 677WUblastx.64 (O75353) ANTI-DEATH PROTEIN. O75353 72% 44 259 98% 250 498HAWAS41 877621 678 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 66%754 930 PROTEIN. HAWBA65 542056 679 WUblastx.64 (Q24333) ELASTIN LIKEPROTEIN Q24333 100% 41 112 (FRAGMENT). HBAGH64 801884 680 WUblastx.64(Q14287) HYPOTHETICAL Q14287 37% 810 568 PROTEIN (FRAGMENT). HBBBA42841010 684 WUblastx.64 (Q9UIL1) HRIHFB2072 PROTEIN Q9UIL1 58% 3 263(FRAGMENT). 57% 6 269 HBCAQ48 525002 690 WUblastx.64 (O75528) ADA3-LIKEPROTEIN. O75528 84% 73 345 HBGBE75 897455 694 WUblastx.64 (O60830)MITOCHONDRIAL I17B_HUMAN 97% 98 307 IMPORT INNER MEMBRANE TRANSLOCASE SUHBHAA53 603183 699 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 65% 439326 PRODUCT. 68% 594 415 HBIAU43 840354 700 WUblastx.64 (Q9UI59) PRO0478PROTEIN. Q9UI59 76% 1109 1225 HBIAW58 596805 701 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 66% 1268 1188 CLONE COL04765. 77% 1335 127068% 1486 1337 HBIBF26 845743 703 WUblastx.64 (Q9NQQ7) BA394O2.1 (CGI-15Q9NQQ7 76% 1214 1405 PROTEIN). 74% 804 1223 47% 780 845 78% 313 825HBIBQ69 580807 706 WUblastx.64 (BAB55217) CDNA FLJ14686 fis, BAB5521794% 671 724 clone NT2RP2004961, m 100% 721 810 HBIBR38 612783 707WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 73% 802 503 CLONEKAT08285. HBIBS33 590280 709 WUblastx.64 (Q9H960) CDNA FLJ12988 FIS,Q9H960 62% 595 452 CLONE NT2RP3000080. HBIBZ20 688861 711 WUblastx.64(O75717) ACIDIC O75717 99% 229 603 NUCLEOPLASMIC DNA-BINDING PROTEIN 1(AND-1). HBICB80 637516 712 WUblastx.64 (Q9BV17) SIMILAR TO CG9172Q9BV17 90% 545 637 GENE PRODUCT. 91% 18 557 HBJAC40 841235 713WUblastx.64 (Q9P112) CHROMOSOME 16 OPEN Q9P112 100% 8 73 READING FRAME5. 36% 5 70 57% 11 52 53% 85 180 100% 192 632 HBJAV56 603529 714WUblastx.64 (Q9H387) PRO2550. Q9H387 58% 642 478 67% 715 623 75% 780 745HBJBR40 581104 717 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 54%931 860 PROTEIN. 66% 861 745 HBJCH46 609859 718 WUblastx.64 conservedhypothetical protein pir|D83014|D83014 53% 1070 900 PA5065 [imported] -Pseudomonas 78% 900 1 aeruginosa (strain PAO1) HBJCS26 821682 720WUblastx.64 (Q9H0D4) HYPOTHETICAL 54.1 KDA Q9H0D4 92% 227 1576 PROTEIN.HBJDR18 604907 723 WUblastx.64 (Q9H6G8) CDNA: FLJ22294 FIS, Q9H6G8 81%940 875 CLONE HRC04426. 77% 1092 934 HBJDR83 600395 724 WUblastx.64(Q14273) POL/ENV ORF. Q14273 71% 559 621 60% 813 902 68% 614 718 41%1223 1291 62% 14 556 HBJEL21 866158 726 WUblastx.64 (Q9UQR1) ZINC FINGERPROTEIN Z148_HUMAN 97% 807 2063 148 (ZINC FINGER DNA BINDING P HBJFH84836997 727 WUblastx.64 (Q9LM25) T10O22.22. Q9LM25 30% 118 921 HBJFJ26873844 3102 WUblastx.64 (Q9BWK5) UNKNOWN (PROTEIN Q9BWK5 94% 657 758 FORMGC: 5242). 100% 336 389 100% 427 657 HBJHO83 610259 736 HMMER PFAM: ENVpolyprotein (coat PF00429 40.5 207 389 2.1.1 polyprotein) WUblastx.64(Q85641) 3′ END OF THE GENOME Q85641 85% 2 61 OF MOLONEY MURINE 28% 177365 LEUKEMIA VIRUS (CODES 46% 64 180 HBJIR14 793391 741 WUblastx.64(Q9H832) CDNA FLJ13968 FIS, Q9H832 91% 134 871 CLONE Y79AA1001493,WEAKLY SIMILAR TO UBI HBJJA26 743181 742 WUblastx.64 (Q9BRM8) UNKNOWN(PROTEIN Q9BRM8 47% 647 423 FOR MGC: 13219). HBJND04 837242 745 HMMERPFAM: Bacterial mutT protein PF00293 26.2 −360 −479 2.1.1 WUblastx.64(Q9BW91) UNKNOWN (PROTEIN Q9BW91 91% 309 1352 FOR MGC: 3037). HBJND57612785 746 WUblastx.64 (Q9VCB4) CG17741 PROTEIN. Q9VCB4 52% 1 318HBKEE60 793788 749 WUblastx.64 pro-pol-dUTPase polyprotein - murinepir|T29097|T29097 64% 97 204 endogenous retrovirus ERV-L 39% 3 128(fragment) 62% 273 620 HBKEI41 827278 750 WUblastx.64 (BAB47402)CG10671-like. BAB47402 100% 436 465 90% 596 757 59% 498 623 77% 5 436HBMBD51 842176 751 WUblastx.64 hypothetical protein pir|T50632|T5063298% 2197 2709 DKFZp762E1511.1 - human (fragment) HBMBD73 839564 752WUblastx.64 MAP kinase 1 (EC 2.7.1.—) - human pir|JQ1400|JQ1400 91% 93161 92% 127 1137 HBMBM17 637518 754 WUblastx.64 (Q9NX85) CDNA FLJ20378FIS, Q9NX85 75% 950 840 CLONE KAIA0536. 75% 1083 949 HBMCL59 608668 755WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 45% 630 472 CLONECOL04765. 60% 796 608 HBMCM96 821318 756 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 57% 2253 2155 CLONE COL04765. 63% 2177 1971 HBMCQ74856461 757 WUblastx.64 (Q9JKP5) MUSCLEBLIND. Q9JKP5 100% 561 590 52% 13213 83% 1 465 HBMCQ74 864382 758 WUblastx.64 (Q9JKP5) MUSCLEBLIND.Q9JKP5 100% 561 590 52% 13 213 83% 1 465 HBMDM08 837927 760 WUblastx.64(Q9P0I2) 30 KDA PROTEIN. Q9P0I2 94% 190 972 HBMSO30 843389 762WUblastx.64 (Q9D4B1) 4933405A16RIK Q9D4B1 78% 52 174 PROTEIN. HBMTM50609988 763 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 76% 763 689CLONE KAIA0536. 55% 962 765 HBMUD59 701970 764 WUblastx.64 (Q9BR03)C367G8.2 (NOVEL Q9BR03 91% 9 647 PROTEIN) (FRAGMENT). HBMUR39 647594 767WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 55% 883 803 PRODUCT. 39% 810577 HBMWC39 523713 770 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H72871% 1055 1117 CLONE COL04765. 67% 820 1053 HBMWS52 872553 772WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 62% 1341 997 CLONECOL04765. HBMXG01 689522 774 WUblastx.64 (Q9BGX7) HYPOTHETICAL 13.0 KDAQ9BGX7 58% 838 885 PROTEIN. 71% 900 1055 HBMXG76 580812 775 WUblastx.64probable phosphodiesterase I (EC pir|T43461|T43461 98% 37 222 3.1.4.1) -human (fragment) HBMXW83 725335 777 WUblastx.64 glutamate-cysteineligase (EC 6.3.2.2) pir|JH0611|JH0611 100% 492 584 heavy chain - human90% 373 498 HBNAE74 637524 778 WUblastx.64 (Q9NU78) DJ622L5.7.1 (NOVELQ9NU78 100% 6 146 PROTEIN (ISOFORM 1)). HBNAX16 843727 779 WUblastx.64(Q9BT21) SIMILAR TO RIKEN Q9BT21 92% 360 2639 CDNA 2610005L19 GENE(FRAGMENT). HBODK40 852382 781 WUblastx.64 (Q9Y6B7) ADAPTER-RELATEDA4B1_HUMAN 89% 55 696 PROTEIN COMPLEX 4 BETA 1 99% 674 1741 SUBUNIT (HBODV76 866420 782 WUblastx.64 (O60662) KELCH-RELATED KRP1_HUMAN 83% 474902 PROTEIN 1 (KEL-LIKE PROTEIN 100% 71 475 23) (SAR 96% 808 1905HBPAF39 850786 784 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 51%1217 849 CLONE KAIA0536. HBQAC72 799512 786 WUblastx.64 transcriptionfactor znf6 - human pir|S25409|S25409 90% 2072 1110 33% 1844 1227 30%2024 1215 30% 1757 1194 31% 1844 1401 HBSAJ63 848683 788 WUblastx.64(BAB55144) CDNA FLJ14576 fis, BAB55144 92% 11 406 clone NT2RM4001092, wHBSDD24 839802 790 WUblastx.64 (Q9UJ70) N- Q9UJ70 100% 886 1251ACETYLGLUCOSAMINE KINASE PROTEIN (EC 2.7.1.59). HBWBD25 800765 791WUblastx.64 (O08872) PUTATIVE RNA O08872 49% 850 698 BINDING PROTEIN 130% 1473 853 (FRAGMENT). HBXAS93 836513 792 WUblastx.64 (Q14940)SODIUM/HYDROGEN NAH5_HUMAN 85% 532 1023 EXCHANGER 5 (NA(+)/H(+) 78% 2238 EXCHANGER 90% 256 321 HBXAW57 815650 794 WUblastx.64 (Q9N083)UNNAMED PORTEIN Q9N083 56% 1223 1071 PRODUCT. HBXBM78 812527 797WUblastx.64 (Q9Y613) FH1/FH2 DOMAINS- FHOS_HUMAN 84% 846 259 CONTAININGPROTEIN (FORMIN 28% 2503 2138 HOMOLOG 100% 1004 852 97% 1903 1046 100%2311 2042 42% 2184 2122 28% 1777 1334 55% 2520 2248 HBXCD59 860439 798WUblastx.64 (Q9C026) TRIPARTITE MOTIF Q9C026 99% 59 823 PROTEIN TRIM9ISOFORM BETA. HBXCG08 628501 800 WUblastx.64 (Q9BSG3) UNKNOWN (PROTEINQ9BSG3 98% 758 1024 FOR MGC: 12974). HBXCM52 799513 801 WUblastx.64(Q9BH03) HYPOTHETICAL 12.0 KDA Q9BH03 53% 683 850 PROTEIN. 73% 784 94280% 903 1028 HBXCQ03 589516 802 WUblastx.64 (Q9Y296) PTD009 (HSPC172).Q9Y296 100% 382 672 100% 17 382 HBXDN08 566765 806 WUblastx.64 (O43597)SPROUTY HOMOLOG 2 SPY2_HUMAN 100% 8 256 (SPRY-2). HBXDN65 840021 807WUblastx.64 (Q9H387) PRO2550. Q9H387 75% 1925 1641 HBXFA04 842901 808WUblastx.64 (AAH08467) Similar to RIKEN cDNA AAH08467 95% 287 4991110001J03 gene. HBXFE64 838824 809 WUblastx.64 (Q9H728) CDNA: FLJ21463FIS, Q9H728 57% 1646 1320 CLONE COL04765. HBXFP72 688040 811 WUblastx.64(Q9H754) CDNA: FLJ21308 FIS, Q9H754 93% 7 1155 CLONE COL02131. HBXFS31815651 812 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 65% 469 678CLONE KAT08285. 70% 1551 1261 HBXFW01 847001 813 HMMER PFAM: Stathminfamily PF00836 185.7 266 523 2.1.1 WUblastx.64 (Q9H169) RB3 PROTEINQ9H169 100% 523 690 (HYPOTHETICAL 22.1 KDA 100% 125 523 PROTEIN).HBXGE12 1310891 814 WUblastx.64 (O95902) UNKNOWN O95902 100% 31 411(FRAGMENT). HBXGE12 745398 3103 WUblastx.64 (AF131851) Unknown [Homosapiens] gb|AAD20061.1| 100% 10 390 HBXGL91 901845 815 WUblastx.64(Q9H2J7) ORPHAN Q9H2J7 100% 949 1470 NEUROTRANSMITTER 100% 10 99TRANSPORTER V7-3. 95% 389 979 HBXGM24 821320 816 WUblastx.64hypothetical protein (L1H 3′ region) - pir|B34087|B34087 77% 712 647human 46% 740 660 48% 639 475 57% 85 23 64% 530 84 HCBAB34 847002 821WUblastx.64 (Q9BWF8) UNKNOWN (PROTEIN Q9BWF8 95% 1009 1308 FOR IMAGE:3355813) 98% 814 963 (FRAGMENT). 95% 680 823 60% 29 583 HCDAH02 653066825 WUblastx.64 (BAB55208) CDNA FLJ14668 fis, BAB55208 81% 655 491 cloneNT2RP2003194. 83% 492 241 HCDAP33 566794 826 WUblastx.64 (O75964) ATPSYNTHASE G ATPN_HUMAN 73% 407 664 CHAIN, MITOCHONDRIAL (EC 3.6.1.34)HCDAR40 654821 827 WUblastx.64 (Q9P195) PRO1722. Q9P195 63% 837 514HCDAS02 896667 828 WUblastx.64 (O75153) PUTATIVE EUKARYOTIC IF3X_HUMAN89% 79 867 TRANSLATION INITIATION FACTOR HCDBO32 831942 830 WUblastx.64(AAH17472) Hypothetical 21.3 kDa AAH17472 69% 643 801 protein. 100% 239583 HCDBW67 733860 831 WUblastx.64 (Q9H410) DJ469A13.2 (NOVEL Q9H410 97%43 255 PROTEIN) (FRAGMENT). HCDCB03 571037 833 HMMER PFAM: Zinccarboxypeptidase PF00246 103.3 35 337 2.1.1 WUblastx.64 carboxypeptidaseH (EC 3.4.17.10) pir|S09489|S09489 91% 657 728 precursor - human 66% 11664 HCDCE51 813504 834 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 55%1016 837 PRODUCT. HCDCI42 847004 835 WUblastx.64 (Q9UHD2) TANK BINDINGQ9UHD2 100% 678 875 KINASE TBK1 (NF-KB- ACTIVATING KINASE NAK). HCDDB15841041 836 WUblastx.64 (Q9BW53) UNKNOWN (PROTEIN Q9BW53 100% 98 703 FORIMAGE: 3343149) (FRAGMENT). HCDDY28 892137 838 WUblastx.64 (Q14287)HYPOTHETICAL Q14287 55% 1458 1312 PROTEIN (FRAGMENT). 60% 1312 1013HCDEB19 587264 839 WUblastx.64 nuclear matrix protein NMP 238 -pir|JE0334|JE0334 100% 1218 1436 human 93% 426 470 99% 473 829 98% 76438 31% 605 700 31% 1335 1430 91% 838 1218 HCDES69 609997 841WUblastx.64 (Q9H8N2) CDNA FLJ13381 FIS, Q9H8N2 61% 524 423 CLONEPLACE1001010. 62% 687 553 HCE1D45 664481 842 WUblastx.64 (Q9UDU0) WUGSC:H_DJ400N23.1 Q9UDU0 84% 10 279 PROTEIN (ZINC FINGER SARCOMA GENE LONG AHCE1T53 843680 844 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 71%725 663 CLONE KAT08285. 65% 843 739 92% 1450 1412 67% 1409 1140 HCE1Y27637529 845 WUblastx.64 (O95741) COPINE VI (NEURONAL- CNE6_HUMAN 80% 887946 COPINE) (N-COPINE). 98% 519 896 95% 901 1353 93% 16 561 HCE1Y34809084 846 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 61% 1718 1680CLONE KAIA0536. 51% 1680 1411 HCE2E47 886155 848 WUblastx.64 (Q9H387)PRO2550. Q9H387 72% 1254 1448 67% 1450 1533 HCE2P90 737935 850WUblastx.64 (AAH07558) Unknown (protein for AAH07558 47% 792 896 MGC:15483). 42% 640 795 HCE3C46 737889 852 WUblastx.64 (Q9NX17) CDNAFLJ20489 FIS, Q9NX17 41% 186 260 CLONE KAT08285. 62% 751 1032 HCE3D58873227 853 WUblastx.64 (Q9H026) HYPOTHETICAL 16.0 KDA Q9H026 70% 421 879PROTEIN (FRAGMENT). HCE3N23 810211 857 WUblastx.64 (Q9D2L0)4833417L20RIK Q9D2L0 42% 1150 1539 PROTEIN. 38% 1147 1536 71% 423 59070% 913 1044 55% 584 925 54% 916 1047 44% 370 423 58% 863 913 72% 77 358HCE3R01 834836 858 WUblastx.64 (O95251) HISTONE O95251 76% 6 320ACETYLTRANSFERASE. 84% 68 1111 HCE3R01 841472 859 WUblastx.64 (O95251)HISTONE O95251 76% 6 320 ACETYLTRANSFERASE. 84% 68 1111 HCE3R01 844574860 WUblastx.64 (O95251) HISTONE O95251 76% 6 320 ACETYLTRANSFERASE. 84%68 1111 HCE3R46 844450 861 WUblastx.64 (O95894) UNKNOWN (DERP2). O9589491% 131 1165 HCE4H32 843941 862 WUblastx.64 (Q9NVF5) CDNA FLJ10769 FIS,Q9NVF5 92% 926 964 CLONE NT2RP4000151. 65% 964 1104 64% 73 402 94% 333893 HCE4H32 874256 863 WUblastx.64 (Q9P0P1) HSPC237. Q9P0P1 100% 12601322 100% 1325 1765 HCE4W88 792953 865 WUblastx.64 (Q9Y5W4) MLLSEPTIN-LIKE Q9Y5W4 100% 3676 2003 FUSION PROTEIN (CELL DIVISION CONTROLPROTEI HCE5B62 566864 866 WUblastx.64 (O60448) NEURONAL THREAD O6044870% 1011 850 PROTEIN AD7C-NTP. 47% 1056 757 64% 1653 1486 58% 1563 144147% 953 810 70% 1470 1420 34% 820 725 40% 1023 943 62% 956 855 58% 778728 58% 1553 1425 63% 1653 1546 61% 1632 1579 38% 1631 1500 36% 981 74855% 1696 1637 56% 1505 1410 50% 1496 1431 45% 823 725 59% 846 781 61%995 834 43% 1557 1420 84% 1683 1645 62% 1673 1425 HCE5H86 847032 867WUblastx.64 (O95637) WW DOMAIN BINDING O95637 83% 1574 2107 PROTEIN-1.66% 847 1248 66% 1300 1539 HCE5J64 688883 868 WUblastx.64 (Q9GMX5)HYPOTHETICAL 12.9 KDA Q9GMX5 64% 2021 2122 PROTEIN. 56% 1903 2031HCEBF54 847033 869 WUblastx.64 (Q9NQ43) HYPOTHETICAL 18.4 KDA Q9NQ43100% 338 583 PROTEIN (FRAGMENT). HCEDN07 847034 874 WUblastx.64 (Q9H387)PRO2550. Q9H387 93% 1256 1212 86% 1186 1121 71% 1410 1255 HCEEG48 896688876 WUblastx.64 (AAK55521) PRO0764. AAK55521 70% 919 680 HCEEM33 821322877 WUblastx.64 hypothetical protein pir|T46310|T46310 100% 3 746DKFZp434G0511.1 - human HCEFA94 822850 882 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 56% 1066 1224 PROTEIN. HCEFG93 745400 884WUblastx.64 (Q9H387) PRO2550. Q9H387 66% 1178 1134 80% 1114 1052 76%1323 1186 HCEFH31 801890 885 WUblastx.64 (Q9ULW1) SPONDIN 2. Q9ULW1 100%1503 1685 HCEFK56 872554 886 WUblastx.64 (Q9UIU2) DYNACTIN 1 P150 Q9UIU292% 7 2088 ISOFORM. HCEGK81 844452 890 WUblastx.64 (Q9H387) PRO2550.Q9H387 88% 524 649 68% 390 455 76% 487 525 HCEGS49 846298 891WUblastx.64 (O60448) NEURONAL THREAD O60448 42% 711 529 PROTEINAD7C-NTP. 92% 651 610 61% 856 710 72% 870 838 66% 721 659 61% 872 71168% 857 579 HCEGY33 753258 893 WUblastx.64 (O75843) ADAPTER-RELATEDA1G2_HUMAN 97% 1131 988 PROTEIN COMPLEX 1 GAMMA 2 89% 873 760 SUBUNIT100% 1396 1274 68% 393 256 96% 603 523 98% 2024 1818 HCEHW24 560610 894WUblastx.64 (Q9BGX7) HYPOTHETICAL 13.0 KDA Q9BGX7 55% 1001 1297 PROTEIN.HCEJL08 722208 895 WUblastx.64 (AAH08203) Chromosome X open AAH08203 59%36 170 reading frame 12. 96% 581 775 58% 2 103 79% 130 570 HCELB04847375 897 WUblastx.64 (Q9P290) POTENT BRAIN TYPE Q9P290 96% 994 1083ORGANIC ION TRANSPORTER. 94% 156 263 71% 677 1024 100% 317 544 62% 11061177 73% 500 544 75% 1064 1579 HCEMA08 846468 898 WUblastx.64 ATPaseinhibitor precursor, pir|JC7175|JC7175 65% 1599 1739 mitochondrial -human 100% 67 216 HCENQ22 740746 900 WUblastx.64 (Q9H926) CDNA FLJ13059FIS, Q9H926 80% 1086 934 CLONE NT2RP3001589. HCEOF01 564906 901WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 50% 1669 1586 CLONECOL04765. 75% 1551 1366 HCEOF01 850521 902 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 50% 1668 1585 CLONE COL04765. 75% 1550 1365 HCEOV48850681 905 WUblastx.64 (Q9DA75) 1700018O18RIK Q9DA75 83% 1344 1739PROTEIN. 76% 193 1311 HCEPO08 637543 907 WUblastx.64 ribosomal proteinL29, cytosolic - pir|S65784|S65784 100% 614 504 human 64% 516 145HCESB03 812940 908 WUblastx.64 (Q9HD86) NAG18. Q9HD86 76% 729 857HCETL19 702090 911 WUblastx.64 retrovirus-related env polyproteinpir|E24483|VCHUER 79% 580 464 pseudogene - human HCFAT42 815652 915WUblastx.64 (Q9G6T1) CYTOCHROME Q9G6T1 79% 699 884 OXIDASE SUBUNIT 3.47% 369 431 HCFAT66 821337 916 WUblastx.64 (Q9HAD8) CDNA FLJ11786 FIS,Q9HAD8 64% 1754 1662 CLONE HEMBA1006036. 69% 1641 1453 HCFBA30 608166917 WUblastx.64 (Q9BU56) UNKNOWN (PROTEIN Q9BU56 75% 357 692 FOR IMAGE:3940029) 45% 192 245 (FRAGMENT). HCFBM77 604576 918 WUblastx.64 (O60448)NEURONAL THREAD O60448 59% 729 664 PROTEIN AD7C-NTP. 75% 880 719 77% 865605 HCFCB72 824165 920 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX8563% 1537 1370 CLONE KAIA0536. 59% 1707 1555 HCFCG91 897509 921WUblastx.64 (Q9V677) CG8858 PROTEIN. Q9V677 47% 53 511 32% 786 2780 43%492 785 24% 480 950 23% 1269 1565 21% 1275 1643 26% 1800 1922 HCFCM81847378 922 WUblastx.64 (O00398) PUTATIVE PURINERGIC O00398 96% 281 1297RECEPTOR P2Y10. HCFLJ52 1307037 928 WUblastx.64 (O00466) K12 PROTEINO00466 95% 362 418 PRECURSOR. 100% 415 561 100% 121 372 HCFLJ52 7532603104 WUblastx.64 (AX055560) unnamed protein product emb|CAC22100.1| 100%91 126 [Homo sapiens] 56% 14 94 98% 123 287 HCFLY20 786452 932WUblastx.64 hypothetical protein pir|T46299|T46299 85% 57 380DKFZp434J0310.1 - human 93% 437 784 65% 936 1022 40% 167 226 76% 757 936HCFLY20 858875 933 WUblastx.64 hypothetical protein pir|T46299|T4629985% 68 391 DKFZp434J0310.1 - human 72% 959 1033 40% 178 237 89% 448 951HCFMX16 581042 938 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 54%304 29 PROTEIN. HCFMX88 825989 939 WUblastx.64 (Q9HAD8) CDNA FLJ11786FIS, Q9HAD8 71% 1068 1130 CLONE HEMBA1006036. 77% 853 945 69% 959 1066HCFNM40 746864 940 WUblastx.64 catalase (EC 1.11.1.6) -pir|I40767|I40767 84% 246 130 Campylobacter jejuni HCFNM50 732010 941WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 75% 1258 1103 CLONEKAT08285. HCFNN75 762959 943 WUblastx.64 (Q9BGZ4) HYPOTHETICAL 11.6 KDAQ9BGZ4 56% 821 696 PROTEIN. HCGBA15 604603 946 WUblastx.64 (AAK55521)PRO0764. AAK55521 81% 791 726 80% 925 881 80% 724 662 65% 903 790HCHAC68 610370 947 HMMER PFAM: Ank repeat PF00023 58.1 462 560 2.1.1WUblastx.64 (Q9Y290) RELA ASSOCIATED Q9Y290 90% 201 770 INHIBITOR. 93%52 96 100% 770 871 70% 6 50 HCHBP49 892141 948 WUblastx.64 hypotheticalprotein pir|T47147|T47147 91% 8 457 DKFZp761H229.1 - human (fragment)HCHCG33 862534 950 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 66%2068 1988 CLONE COL04765. 75% 2285 2073 HCHMY57 833049 951 WUblastx.64(Q9BV10) UNKNOWN (PROTEIN Q9BV10 84% 12 1202 FOR MGC: 3136). HCHOC06688042 952 WUblastx.64 (Q9BZH7) GASTRIC CANCER- Q9BZH7 75% 131 424RELATED PROTEIN VRG107. HCHOY52 837297 953 WUblastx.64 (Q9BT25) UNKNOWN(PROTEIN Q9BT25 89% 27 1223 FOR IMAGE: 3636299) (FRAGMENT). HCHQB93793648 954 WUblastx.64 GTP-binding protein 2 - human pir|PC7084|PC708489% 767 985 (fragment) 92% 258 788 86% 2 46 37% 36 143 100% 61 258HCHQB93 875853 955 WUblastx.64 GTP-binding protein 2 - humanpir|PC7084|PC7084 89% 767 985 (fragment) 92% 258 788 86% 2 46 37% 36 143100% 61 258 HCLCU75 862406 957 WUblastx.64 (Q24333) ELASTIN LIKE PROTEINQ24333 95% 51 122 (FRAGMENT). HCMSA37 598712 958 WUblastx.64 (Q9UHS7)PRO1992. Q9UHS7 63% 902 795 HCMSR07 821338 959 WUblastx.64 (Q9UI59)PRO0478 PROTEIN. Q9UI59 91% 1388 1489 HCNSF01 901060 964 WUblastx.64(Q9Y6N5) HYPOTHETICAL 50.0 KDA Q9Y6N5 100% 107 1456 PROTEIN. HCPAE41799546 967 WUblastx.64 (Q9P0P0) HSPC238 Q9P0P0 81% 490 443 (HYPOTHETICAL17.9 KDA 73% 444 31 PROTEIN). HCQAS72 828082 970 WUblastx.64 (AAK58423)PC2-glutamine-rich- AAK58423 91% 22 57 associated protein. 93% 1010 1054100% 57 119 71% 122 463 HCQBM95 841011 971 WUblastx.64 ribosomal proteinL39, cytosolic pir|JC4229|R6RT39 84% 409 447 [validated] - rat 88% 282389 HCRAI29 844084 979 WUblastx.64 hypothetical protein (L1H 3′region) - pir|B34087|B34087 34% 329 132 human 56% 48 1 39% 493 305 61%89 12 HCRBL20 709660 981 WUblastx.64 (Q9NWM9) CDNA FLJ20730 FIS, Q9NWM994% 1 678 CLONE HEP10359. HCRBX84 1007105 982 WUblastx.64 (Q9H1F6)DJ453C12.6.1 Q9H1F6 91% 37 177 (UNCHARACTERIZED 63% 51 617 HYPOTHALAMUSPROTEIN (ISOFORM HCRMA24 897005 983 WUblastx.64 hypothetical proteinpir|T08683|T08683 100% 388 591 DKFZp564J2123.1 - human (fragment)HCRMR35 849071 984 WUblastx.64 (Q9H175) HYPOTHETICAL 59.6 KDA Q9H175 48%43 858 PROTEIN. HCRMR35 874743 985 WUblastx.64 (Q9H175) HYPOTHETICAL59.6 KDA Q9H175 48% 43 858 PROTEIN. HCRMR35 897434 986 WUblastx.64(Q9H175) HYPOTHETICAL 59.6 KDA Q9H175 49% 43 858 PROTEIN. HCROC18 884144987 WUblastx.64 (Q9H8A5) CDNA FLJ13824 FIS, Q9H8A5 95% 7 1695 CLONETHYRO1000505. HCUAE53 665716 988 WUblastx.64 hypothetical protein[imported] - pir|E86188|E86188 58% 504 304 Arabidopsis thaliana 80% 22576 56% 895 653 28% 542 459 62% 1299 1156 HCUAT74 834611 990 WUblastx.64hypothetical protein UL126 - human pir|S09875|S09875 68% 3 191cytomegalovirus (strain AD169) HCUBN69 826610 994 WUblastx.64 (Q9BVD9)UNKNOWN (PROTEIN Q9BVD9 78% 831 763 FOR MGC: 5149). 72% 626 573 80% 760626 HCUBY47 842787 995 WUblastx.64 (Q9EPL2) CALSYNTENIN-1 Q9EPL2 97% 444313 PROTEIN PRECURSOR. 97% 1003 869 HCUCV66 806577 996 WUblastx.64(BAB22833) 18 days embryo cDNA, BAB22833 100% 36 362 RIKEN full-length eHCUFC77 745374 1001 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 77%1526 1461 CLONE KAIA0536. 61% 1449 1234 HCUFD17 847039 1002 WUblastx.64(Q9HBZ6) HT005 PROTEIN. Q9HBZ6 100% 10 195 HCUFD46 757481 1003WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 43% 580 386 CLONECOL04765. HCUFX08 612843 1008 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDAQ9BGW3 55% 1214 1128 PROTEIN. 65% 1329 1216 HCUHE27 562766 1014WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 61% 764 639 PRODUCT. HCWAK88839083 1017 WUblastx.64 probable excinuclease ABC chain A -pir|T33732|T33732 86% 435 370 Zymomonas mobilis 31% 815 321 32% 19691814 64% 956 501 67% 362 42 57% 1237 1181 69% 1306 998 85% 1993 1538HCWAL10 639023 1018 WUblastx.64 (Q9Y2N3) NUCLEAR ENVELOPE N121_HUMAN100% 754 680 PORE MEMBRANE PROTEIN POM 100% 240 118 121 (PO HCWDM69684527 1022 WUblastx.64 (Q9P195) PRO1722. Q9P195 66% 819 748 78% 886 81870% 1001 900 HCWEB72 639041 1024 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 56% 872 798 CLONE KAIA0536. 48% 588 508 65% 757 617 HCWEI82799516 1026 WUblastx.64 (Q9P1N7) PRO0974. Q9P1N7 47% 384 656 HCWEM96812735 1027 WUblastx.64 probable ATP-binding component ofpir|G83165|G83165 74% 1901 1146 ABC transporter PA3838 [imported] -Pseudomonas aeruginosa (strain PAO1) HCWHD30 834724 1031 WUblastx.64(AAH07609) Similar to hypothetical AAH07609 86% 634 590 protein PRO1722.80% 782 633 HCWHT34 692400 1032 WUblastx.64 (Q9UI50) PRO0657 (FRAGMENT).Q9UI50 68% 556 777 HCWHT52 834618 1033 WUblastx.64 hypothetical proteinUL126 - human pir|S09875|S09875 75% 20 274 cytomegalovirus (strainAD169) HCWKO32 610619 1034 WUblastx.64 (Q9GMU5) HYPOTHETICAL 14.1 KDAQ9GMU5 82% 496 600 PROTEIN. HCWUW24 799517 1037 WUblastx.64 (Q9H387)PRO2550. Q9H387 45% 541 696 33% 60 245 77% 686 817 HCYBA32 847042 1038WUblastx.64 (Q9H3F8) MSTP016. Q9H3F8 100% 329 718 79% 925 1800 HDABR74861789 1040 WUblastx.64 (O60717) 7- O60717 81% 5 37 DEHYDROCHOLESTEROL95% 69 908 REDUCTASE (EC 1.3.1.21) (FRAGMENT). HDFIB37 821339 1045WUblastx.64 (Q9D8F2) 2010004A03RIK Q9D8F2 74% 792 884 PROTEIN. 64% 357431 65% 388 816 HDHEA33 847044 1048 WUblastx.64 (Q9BU66) UNKNOWN(PROTEIN Q9BU66 40% 482 619 FOR MGC: 10433). 45% 159 638 82% 1054 1494HDHEB12 610260 1049 WUblastx.64 (Q9NZ96) NEUROLIGIN 3 Q9NZ96 94% 2 697ISOFORM HNL3S (FRAGMENT). HDLAL94 843583 1054 HMMER PFAM:ADP-ribosylation factor PF00025 309.2 195 728 2.1.1 family WUblastx.64(Q9D4P0) 4930587A11RIK Q9D4P0 100% 192 728 PROTEIN. HDPAB86 901851 1055WUblastx.64 (Q9NYH9) HEPATOCELLULAR Q9NYH9 56% 74 538CARCINOMA-ASSOCIATED 97% 310 1863 ANTIGEN 66. HDPAE80 778068 1056WUblastx.64 (Q9BR63) PHENYLALANYL-TRNA Q9BR63 93% 1435 1662 SYNTHETASEBETA-SUBUNIT 78% 1604 1744 (FRAGMENT). 54% 383 661 32% 417 761 98% 9051438 HDPAQ86 612855 1057 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, Q9H74348% 1419 1246 CLONE COL03536. 76% 1250 1122 HDPBN48 838593 1059WUblastx.64 (Q9H013) MELTRIN-BETA/ADAM Q9H013 84% 525 773 19 HOMOLOGUE.HDPCG79 691350 1060 WUblastx.64 (Q9H9H4) CDNA FLJ12750 FIS, Q9H9H4 98%415 588 CLONE NT2RP2001168, WEAKLY SIMILAR TO VER HDPCV29 567228 1061WUblastx.64 hypothetical protein (L1H 3′ region) - pir|B34087|B34087 40%546 1196 human HDPDA36 827283 1062 WUblastx.64 (Q9CZU3) 2610528A15RIKQ9CZU3 96% 3443 3604 PROTEIN. HDPDC59 872451 1063 WUblastx.64 (Q9H251)CADHERIN RELATED Q9H251 99% 142 1737 23. 32% 145 1761 33% 130 1737 32%130 1734 32% 112 1740 34% 145 1743 31% 124 1731 30% 145 1743 31% 2561725 31% 145 1755 31% 145 1698 31% 139 1491 30% 658 1737 29% 154 1731HDPFG13 637580 1064 WUblastx.64 (Q9H8S0) CDNA FLJ13287 FIS, Q9H8S0 100%55 441 CLONE OVARC1001161. HDPFZ05 824390 1066 WUblastx.64 (Q9CZC8)2810019K23RIK Q9CZC8 84% 500 658 PROTEIN. HDPGR80 844812 1068WUblastx.64 (Q9BRR6) SIMILAR TO RIKEN Q9BRR6 87% 2434 1067 CDNA2610017G09 GENE. 83% 2556 2377 HDPGU14 832543 1069 WUblastx.64 mda-9protein - human pir|JC6537|JC6537 100% 292 1185 HDPGX09 580818 1070WUblastx.64 (Q9D0M0) 2610002K22RIK Q9D0M0 94% 832 999 PROTEIN. 33% 9951093 91% 1020 1220 HDPIE44 899328 1071 WUblastx.64 (Q9D666)4632417G13RIK Q9D666 62% 102 2453 PROTEIN. HDPIE73 886158 1072WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 58% 1852 2145 CLONECOL04765. HDPIF35 826781 1073 WUblastx.64 (BAB55422) CDNA FLJ14966 fis,BAB55422 100% 1000 887 clone THYRO1000034, w HDPIF65 847047 1074WUblastx.64 (Q9H7Z0) CDNA FLJ14058 FIS, Q9H7Z0 60% 236 12 CLONEHEMBB1000554. HDPIH25 740749 1075 WUblastx.64 (Q9H7Q7) FLJ00010 PROTEINQ9H7Q7 78% 99 539 (FRAGMENT). 100% 876 968 76% 971 2266 98% 536 796 50%2190 2300 75% 796 876 HDPIY31 886159 1076 WUblastx.64 hypotheticalprotein pir|T46448|T46448 72% 1714 1899 DKFZp434N1429.1 - human(fragment) HDPJH72 847048 1077 WUblastx.64 (O15427) MONOCARBOXYLATEMOT4_HUMAN 96% 294 392 TRANSPORTER 4 (MCT 4) (MCT 3). 81% 1204 1473 100%77 295 89% 854 1192 37% 1427 1498 71% 394 855 HDPKC55 822869 1080 HMMERPFAM: Tubulin/FtsZ family PF00091 177.8 108 797 2.1.1 WUblastx.64(Q9UJT1) TUBULIN DELTA CHAIN TBD_HUMAN 100% 102 1460 (DELTA TUBULIN).HDPKD16 897304 1081 WUblastx.64 (AAG10506) 2P domain K+ channel AAG10506100% 246 857 TWIK-2. HDPMC52 847049 1082 WUblastx.64 (Q9Y275) TUMORNECROSIS T13B_HUMAN 98% 67 447 FACTOR LIGAND SUPERFAMILY 100% 7 72MEMBER 13 HDPML04 822851 1083 WUblastx.64 X-linked retinopathy protein(C- pir|A46010|A46010 73% 1403 1326 terminal, clone XEH.8c) - human 68%1327 1223 (fragment) HDPNC21 839263 1085 WUblastx.64 (AAK55521) PRO0764.AAK55521 81% 1290 964 HDPNJ26 852338 1086 WUblastx.64 (Q9CQ35)4921508O11RIK Q9CQ35 67% 115 651 PROTEIN. HDPOD73 876202 1087WUblastx.64 (Q9P195) PRO1722. Q9P195 84% 173 211 60% 16 90 61% 78 185HDPOT33 892319 1088 WUblastx.64 (Q92482) AQUAPORIN 3. AQP3_HUMAN 100% 53928 HDPPB70 874027 1089 WUblastx.64 (Q96DV8) Unknown (protein for Q96DV868% 257 1186 MGC: 3551). HDPPE05 809109 1091 WUblastx.64 (Q9P0G1)HSPC075 (FRAGMENT). Q9P0G1 100% 355 459 100% 64 153 HDPSA70 722216 1092WUblastx.64 (Q9UL01) SQUAMOUS CELL Q9UL01 100% 13 261 CARCINOMA ANTIGENRECOGNIZED BY T CELL. HDPTI49 847052 1097 WUblastx.64 (Q14185) DOCK180PROTEIN. Q14185 79% 927 1190 HDPYE25 636058 1099 WUblastx.64 (O42346)NEURULA-SPECIFIC O42346 73% 3 722 FERRODOXIN REDUCTASE-LIKE PROTEIN.HDQGD06 838076 1100 WUblastx.64 (Q9H1C4) UNC-93 RELATED Q9H1C4 80% 9691535 PROTEIN. 90% 59 463 87% 454 996 HDQGD06 852673 1101 WUblastx.64(Q9H1C4) UNC-93 RELATED Q9H1C4 81% 969 1559 PROTEIN. 90% 59 463 87% 454996 HDQGD06 881280 1102 WUblastx.64 (Q9H1C4) UNC-93 RELATED Q9H1C4 86%59 1537 PROTEIN. HDQGN08 840588 1103 WUblastx.64 (Q9HAD8) CDNA FLJ11786FIS, Q9HAD8 56% 782 510 CLONE HEMBA1006036. HDQGO62 837353 1104WUblastx.64 (Q9D6E9) 2900070E19RIK Q9D6E9 96% 222 515 PROTEIN. HDQPM16886161 1105 WUblastx.64 (Q9DCP9) PROLINE RICH Q9DCP9 76% 145 648 PROTEINEXPRESSED IN BRAIN. HDSAH37 603518 1109 WUblastx.64 (Q9H9U3) CDNAFLJ12547 FIS, Q9H9U3 41% 341 156 CLONE NT2RM4000634. 36% 449 147 35% 344105 HDSAM57 834822 1110 WUblastx.64 (Q9P195) PRO1722. Q9P195 76% 752 69080% 685 623 61% 897 742 HDSAO14 847054 1111 WUblastx.64 (Q9H0I1)HYPOTHETICAL 83.8 KDA Q9H0I1 100% 241 348 PROTEIN. HDSAP15 772712 1113WUblastx.64 (Q9H059) HYPOTHETICAL 99.0 KDA Q9H059 46% 160 378 PROTEIN.HDTAR39 847055 1114 WUblastx.64 (Q9NVH2) HYPOTHETICAL 106.8 KDA Q9NVH2100% 13 273 PROTEIN. 85% 242 772 HDTDA48 809110 1118 WUblastx.64(O15254) PRISTANOYL-COA O15254 98% 149 601 OXIDASE. HDTDE66 610074 1119WUblastx.64 (Q9Y609) LR8. Q9Y609 88% 1 447 HDTDG75 799892 1120WUblastx.64 (Q9H2I8) CDA017. Q9H2I8 100% 434 514 HDTGW76 862012 1123WUblastx.64 (Q9NY74) ETAA16 PROTEIN. Q9NY74 73% 1290 1835 27% 1422 161623% 296 829 82% 20 1234 HDTGZ56 800756 1124 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 54% 27 257 PROTEIN. HDTIM39 886164 1126WUblastx.64 (Q9P0Q9) HSPC217. Q9P0Q9 80% 254 523 35% 302 403 90% 504 788HDTKJ29 840023 1127 HMMER PFAM: Uncharacterized protein family PF01027137.6 184 726 2.1.1 WUblastx.64 (Q9Y3C2) CGI-119 PROTEIN. Q9Y3C2 71% 19732 HE2AC74 901343 1131 WUblastx.64 (AAK53385) G protein gamma 12AAK53385 100% 207 422 subunit. HE2AX36 812337 1135 WUblastx.64 (Q9Y5B5)UBIQUITIN-SPECIFIC Q9Y5B5 85% 1292 300 PROTEASE HOMOLOG. HE2AY96 7968001136 WUblastx.64 (BAB22850) 18 days embryo cDNA, BAB22850 87% 56 751RIKEN full-length e HE2BD72 600349 1137 WUblastx.64 (Q9NX85) CDNAFLJ20378 FIS, Q9NX85 66% 496 371 CLONE KAIA0536. 77% 650 522 HE2BH50847056 1138 WUblastx.64 (Q9GZW0) DJ604K5.1 (15 KDA Q9GZW0 100% 226 405SELENOPROTEIN). HE2CC17 566806 1140 WUblastx.64 (Q9HBW6) NAG13. Q9HBW669% 996 694 59% 731 516 75% 347 180 42% 1037 933 70% 540 352 HE2CJ53637592 1141 WUblastx.64 (Q9NUM3) CDNA FLJ11274 FIS, Q9NUM3 100% 123 266CLONE PLACE1009368, WEAKLY 100% 266 412 SIMILAR TO MET HE2DI16 6040291145 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 66% 1350 1201 CLONEKAIA0536. 76% 1483 1331 HE2DJ84 746643 1146 WUblastx.64 (P82673)MITOCHONDRIAL 28S P82673 100% 2 313 RIBOSOMAL PROTEIN S28 (MRP- S28).HE2DY23 877491 1147 WUblastx.64 (Q9VW97) CG17149 PROTEIN. Q9VW97 48%1018 1284 HE2EH45 581520 1150 WUblastx.64 (Q9H3F4) MSTP030. Q9H3F4 73%690 815 63% 8 250 75% 97 735 HE2FE89 780314 1151 WUblastx.64 (Q9QYN1)ENH3. Q9QYN1 95% 254 541 HE2FR49 714456 1152 WUblastx.64 (Q9NUP7) CDNAFLJ11219 FIS, Q9NUP7 64% 63 104 CLONE PLACE1008122. 100% 92 400 HE2GB19566808 1153 WUblastx.64 (O95245) ENVELOPE PROTEIN O95245 41% 397 519(FRAGMENT). 39% 246 362 63% 140 247 HE2HB61 798113 1155 WUblastx.64(Q9BS71) UNKNOWN (PROTEIN Q9BS71 100% 261 365 FOR MGC: 12301). HE2HF76637594 1157 WUblastx.64 (Q9HAZ1) PROTEIN SERINE Q9HAZ1 100% 11 859THREONINE KINASE CLK4. HE21E66 830436 1159 WUblastx.64 (AAH22050)Hypothetical 61.5 kDa AAH22050 98% 98 523 protein (Fragment) HE2NW57638615 1160 WUblastx.64 (Q9UI58) PRO0483 PROTEIN. Q9UI58 57% 191 15HE2OA95 637595 1161 WUblastx.64 (Q9UIK5) TMEFF2 PROTEIN Q9UIK5 99% 16471231 PRECURSOR (TRANSMEMBRANE PROTEIN TENB2) (TPEF HE2PB61 847379 1163WUblastx.64 (Q9BWY7) DJ639P13.1 (NOVEL Q9BWY7 92% 3 719 PROTEIN SIMILARTO RAT TRANSPORTER-LIKE PR HE2PI43 847380 1164 WUblastx.64 (Q9H8E8) CDNAFLJ13697 FIS, Q9H8E8 100% 234 407 CLONE PLACE2000172. HE6CJ41 6049081166 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 54% 898 1050PROTEIN. HE6EI30 847381 1169 WUblastx.64 (Q9BRG1) SIMILAR TO RIKENQ9BRG1 100% 603 523 CDNA 1110020N13 GENE. HE8BP64 847059 1176WUblastx.64 (Q9DBS0) HIPPOCAMPUS Q9DBS0 71% 10 1299 ABUNDANT GENETRANSCRIPT 1. HE8BQ49 589443 1177 WUblastx.64 hypothetical protein -human pir|S72482|S72482 75% 343 474 transposon MER37 64% 105 248 HE8BR18731933 1178 WUblastx.64 (Q9NW38) CDNA FLJ10335 FIS, Q9NW38 100% 654 1091CLONE NT2RM2000669. HE8BT58 806144 1180 WUblastx.64 (Q9BX67) JUNCTIONALQ9BX67 91% 80 937 ADHESION MOLECULE 3 PRECURSOR. HE8CC34 753266 1183WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 72% 2116 1829 CLONECOL04765. HE8DK52 658676 1186 WUblastx.64 (Q9D1U5) D730039F16RIK Q9D1U566% 778 813 PROTEIN. 64% 843 935 HE8DZ94 877630 1187 WUblastx.64(Q9Y3C2) CGI-119 PROTEIN. Q9Y3C2 91% 1295 1657 HE8EX86 823176 1189WUblastx.64 (AAK53401) Elongation factor G2. AAK53401 100% 1410 457 96%2790 2593 88% 2579 1362 HE8FC10 693908 1190 HMMER PFAM: Zinc finger,C2H2 type PF00096 72.8 606 674 2.1.1 WUblastx.64 (Q9H8L4) CDNA FLJ13479FIS, Q9H8L4 84% 300 731 CLONE PLACE1003738, WEAKLY 98% 6 173 SIMILAR TOZIN 45% 438 731 45% 438 674 44% 438 674 39% 438 674 36% 438 674 40% 444674 37% 438 674 37% 444 674 51% 6 134 48% 6 161 46% 6 134 46% 6 134 47%9 134 48% 6 134 47% 9 134 40% 9 134 44% 48 134 HE8FG15 799520 1191WUblastx.64 (O43491) PROTEIN 4.1-G. O43491 84% 226 1197 HE8FG24 7335601192 WUblastx.64 (Q9HAQ1) GLYCEROL 3- Q9HAQ1 90% 11 76 PHOSPHATEPERMEASE. 86% 94 522 HE8FK78 852180 1193 WUblastx.64 (Q9H8A3) CDNAFLJ13837 FIS, Q9H8A3 100% 1 75 CLONE THYRO1000748, 80% 72 266 MODERATELYSIMILAR TO 88% 269 1372 HE8FR53 843807 1196 WUblastx.64 (Q9H373)PRO1107. Q9H373 98% 3411 3181 HE8MQ01 886800 1199 WUblastx.64 (Q9UHT1)PRO1902 PROTEIN. Q9UHT1 71% 2692 2483 HE8MS43 799521 1200 WUblastx.64(Q9D7J4) 2310005N03RIK Q9D7J4 88% 1023 946 PROTEIN. 83% 1247 1155 77%175 44 HE8NC81 862015 1202 WUblastx.64 (Q9H6B2) CDNA: FLJ22418 FIS,Q9H6B2 100% 74 106 CLONE HRC08590. 88% 168 923 HE8NC81 1096692 3106HMMER PFAM: Immunoglobulin domain PF00047 28.3 563 814 2.1.1 WUblastx.64(Q9H6B2) CDNA: FLJ22418 FIS, Q9H6B2 99% 419 1264 CLONE HRC08590. HE8QU21838391 1204 WUblastx.64 (Q9BGZ4) HYPOTHETICAL 11.6 KDA Q9BGZ4 44% 13911125 PROTEIN. HE8SH74 833053 1205 WUblastx.64 (Q9H387) PRO2550. Q9H38769% 2476 2441 50% 3129 3034 76% 3017 2868 HE8UX34 838170 1206WUblastx.64 (Q9H8Q9) CDNA FLJ13310 FIS, Q9H8Q9 67% 7 162 CLONEOVARC1001453. HE9CI81 734918 1209 WUblastx.64 (Q9DB52) 2900009I07RIKQ9DB52 82% 2273 2016 PROTEIN. HE9CJ38 565082 1210 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 64% 1180 1079 PROTEIN. 54% 1380 1243HE9CN58 562768 1212 WUblastx.64 (Q99710) YY1-ASSOCIATED Q99710 44% 6 353FACTOR 2. HE9CV59 847061 1213 WUblastx.64 (Q9CYF7) 5730494N06RIK Q9CYF776% 73 408 PROTEIN. HE9DG54 821326 1214 WUblastx.64 (Q9N083) UNNAMEDPORTEIN Q9N083 53% 1508 1197 PRODUCT. HE9DH59 886059 1215 WUblastx.64(AAK49519) Putative mitochondrial AAK49519 100% 54 419 solute carrier sp94% 1534 2085 HE9EM54 560627 1218 WUblastx.64 (Q9H743) CDNA: FLJ21394FIS, Q9H743 57% 611 688 CLONE COL03536. 67% 756 902 HE9FH28 633737 1219WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 58% 965 591 CLONECOL04765. HE9HE13 868829 1220 WUblastx.64 (Q9P183) PRO2160. Q9P183 100%434 183 HE9HE13 824328 1221 WUblastx.64 (Q9UI56) PROTEIN PRO0518.P518_HUMAN 100% 665 462 HE9HF59 664485 1222 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 45% 1593 1276 PROTEIN. HE9TA42 834972 1227WUblastx.64 (P53992) PROTEIN TRANSPORT S24C_HUMAN 100% 1423 1674 PROTEINSEC24C (SEC24- 98% 2099 2359 RELATED PR 85% 1674 2105 29% 1833 1943 38%58 135 98% 8 1435 HEAAC21 581048 1228 WUblastx.64 (Q9NV24) CDNA FLJ10980FIS, Q9NV24 100% 100 246 CLONE PLACE1001570. HEAAD63 603321 1231WUblastx.64 (Q9H965) CDNA FLJ12983 FIS, Q9H965 84% 613 575 CLONENT2RP3000002. 68% 789 613 HEAAM96 562769 1234 WUblastx.64 (Q9H4S5)DJ336K20B.1 (NOVEL Q9H4S5 83% 541 1044 PROTEIN BASED ON FGENESH)(FRAGMENT). HEAAN52 862020 1235 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5KDA Q9BGW3 54% 796 1104 PROTEIN. HEAAW94 847340 1238 WUblastx.64(Q9UEV9) ACTIN-BINDING Q9UEV9 94% 285 890 PROTEIN HOMOLOG ABP-278. 41%285 884 38% 285 884 36% 285 872 35% 285 884 34% 285 884 34% 285 878 32%303 887 33% 285 881 33% 285 878 31% 285 869 29% 288 887 30% 279 884 31%285 863 36% 414 848 30% 288 884 32% 429 857 31% 309 824 26% 321 824 38%285 539 37% 552 824 HEBAT05 637602 1240 WUblastx.64 (Q9NWW0) CDNAFLJ20568 FIS, Q9NWW0 96% 111 380 CLONE REC00775. 87% 84 131 HEBCN80596808 1243 WUblastx.64 (Q9BGX7) HYPOTHETICAL 13.0 KDA Q9BGX7 57% 782865 PROTEIN. 53% 666 788 HEEAF49 880521 1254 WUblastx.64 (Q9P147)PRO2822. Q9P147 79% 2117 1896 HEEAJ46 637623 1255 WUblastx.64 (AAK55521)PRO0764. AAK55521 86% 2358 2314 66% 1626 1582 55% 2336 2163 73% 16011368 HEGAI20 825818 1256 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 63%893 759 PRODUCT. HEIAC52 826611 1257 WUblastx.64 (Q9H6A7) CDNA: FLJ22429FIS, Q9H6A7 75% 40 915 CLONE HRC09084. HELAT58 732199 1259 WUblastx.64(Q9H743) CDNA: FLJ21394 FIS, Q9H743 56% 1807 1881 CLONE COL03536. 60%1731 1805 59% 1880 2035 HELAW94 834796 1260 WUblastx.64 (AAH02585) RAB7,member RAS AAH02585 100% 159 551 oncogene family-like 1. HELDF80 7995221261 WUblastx.64 N-ras upstream protein NRU - human pir|S29815|S2981599% 3 1289 28% 6 1061 28% 435 1118 HELDK79 532597 1263 WUblastx.64 L6surface protein - human pir|A42926|A42926 78% 71 676 HELDQ42 695716 1264WUblastx.64 (O60629) BLADDER CANCER- BC10_HUMAN 100% 289 549 ASSOCIATEDPROTEIN (BLADDER CANCER HELEL76 862490 1266 WUblastx.64 (Q9BRX8) SIMILARTO RIKEN Q9BRX8 93% 171 818 CDNA 5730469M10 GENE. HELEL76 839470 1267WUblastx.64 (Q9BRX8) SIMILAR TO RIKEN Q9BRX8 98% 545 694 CDNA 5730469M10GENE. 90% 48 506 HELEO45 847067 1268 WUblastx.64 (Q9H6Q6) CDNA: FLJ21982FIS, Q9H6Q6 92% 1385 1423 CLONE HEP06188. 88% 7 1392 HELFA57 845981 1269WUblastx.64 (O95761) WUGSC: H_DJ0771P04.2 O95761 95% 340 1362 PROTEIN(FRAGMENT). 95% 9 137 78% 62 409 HELHN47 872795 1273 WUblastx.64(Q9NWC8) HYPOTHETICAL 17.6 KDA Q9NWC8 91% 1233 772 PROTEIN. HELHP11638064 1274 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, Q9H743 76% 14291313 CLONE COL03536. HELHP11 851116 1275 WUblastx.64 (Q9H743) CDNA:FLJ21394 FIS, Q9H743 79% 1441 1313 CLONE COL03536. HEMBV40 847069 1277WUblastx.64 NADH dehydrogenase (ubiquinone) pir|JC5822|JC5822 77% 7981055 (EC 1.6.5.3) CI-B12 chain - human HEMCJ80 765041 1278 WUblastx.64(Q9NXF8) CDNA FLJ20279 FIS, Q9NXF8 98% 489 710 CLONE HEP03229. 73% 3 20679% 155 487 HEMDB07 617137 1280 WUblastx.64 (Q9H387) PRO2550. Q9H387 82%400 660 HEMGK71 847374 1282 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 80% 1383 1258 CLONE KAIA0536. 64% 1576 1352 HEOMU44 778085 1287WUblastx.64 (Q9N307) HYPOTHETICAL Q9N307 52% 823 1392 PROTEIN Y61A9LA.B.HEONI85 566833 1288 WUblastx.64 hypothetical 43.5K protein - mousepir|JU0319|JU0319 77% 236 421 90% 382 672 HEONK04 658682 1289WUblastx.64 (Q9UKN4) BRIDGING Q9UKN4 72% 267 1070 INTEGRATOR-2. HEONP08601691 1290 WUblastx.64 (Q9Y349) HYPOTHETICAL 15.7 KDA Q9Y349 100% 924523 PROTEIN. HEPBC23 799985 1292 WUblastx.64 (Q9H1V4) DJ1182A14.3(SIMILAR Q9H1V4 92% 4 303 TO MST1 (MACROPHAGE STIMULATING 1 (HEPAHEPCU48 805585 1295 WUblastx.64 (Q9UNT2) PROTEIN O- Q9UNT2 79% 315 1490MANNOSYL-TRANSFERASE 1. 95% 79 324 100% 15 32 HEQAH47 877634 1296WUblastx.64 hypothetical protein pir|T08772|T08772 100% 630 1085DKFZp586M121.1 - human 87% 12 476 (fragment) 30% 90 308 30% 189 305 29%1104 1355 28% 30 245 63% 257 289 HEQBJ01 861786 1300 WUblastx.64(Q9LVQ7) ZINC FINGER PROTEIN. Q9LVQ7 34% 424 849 HEQBJ01 876546 1301WUblastx.64 (Q9LVQ7) ZINC FINGER PROTEIN. Q9LVQ7 34% 424 849 HEQBM94580823 1302 WUblastx.64 (Q9BT25) UNKNOWN (PROTEIN Q9BT25 100% 470 559FOR IMAGE: 3636299) 72% 583 843 (FRAGMENT). 77% 7 471 HESAG57 8559361307 WUblastx.64 (O43432) EIF4GII. O43432 82% 936 7 100% 1221 1030 100%1365 1336 27% 1382 1254 28% 1545 1327 HETBJ88 855937 1310 WUblastx.64(Q9H1Y3) DJ317G22.2 Q9H1Y3 83% 10 864 (ENCEPHALOPSIN) (PANOPSIN).HETCM67 861909 1311 HMMER PFAM: Disintegrin PF00200 112.2 239 466 2.1.1WUblastx.64 (Q9UKQ2) ADAM 28 PRECURSOR AD28_HUMAN 96% 11 1318 (EC3.4.24.—) (A DISINTEGRIN AND HETDD61 800668 1312 WUblastx.64 (Q9Y6B7)ADAPTER-RELATED A4B1_HUMAN 96% 789 1085 PROTEIN COMPLEX 4 BETA 1 85% 363569 SUBUNIT ( 96% 1315 1761 HETDD61 852381 1313 WUblastx.64 (Q9Y6B7)ADAPTER-RELATED A4B1_HUMAN 96% 1314 1760 PROTEIN COMPLEX 4 BETA 1 96%789 1085 SUBUNIT ( 85% 363 569 HETDP76 782836 1316 WUblastx.64 (Q9BUK6)HYPOTHETICAL 61.8 KDA Q9BUK6 100% 29 394 PROTEIN. 92% 700 1620 80% 18952116 53% 1428 1466 100% 465 653 HETFO57 844190 1317 WUblastx.64 (Q9H229)RAD50-INTERACTING Q9H229 96% 2 1363 PROTEIN 1. HFAAI17 607563 1322WUblastx.64 (Q9H387) PRO2550. Q9H387 61% 426 518 73% 281 403 HFADF41607557 1324 WUblastx.64 B-cell growth factor precursor - humanpir|A47582|A47582 56% 600 737 HFADM09 899435 1325 WUblastx.64 ISOFORM 8OF Q9Y4J8 sp_vs|Q9Y4J8- 100% 382 480 02|Q9Y4J8 HFAUA23 636071 1326WUblastx.64 (Q9HAL3) CDNA FLJ11393 FIS, Q9HAL3 25% 243 91 CLONEHEMBA1000591, WEAKLY 45% 466 263 SIMILAR TO PTB HFCAG75 834834 1327WUblastx.64 (AAK55521) PRO0764. AAK55521 80% 745 701 78% 720 484 HFCAI40866441 1328 HMMER PFAM: TPR Domain PF00515 52.6 167 253 2.1.1WUblastx.64 (Q9V532) CG8777 PROTEIN. Q9V532 36% 20 1021 HFCAQ17 6957201329 WUblastx.64 NADH dehydrogenase (ubiquinone) pir|JE0379|JE0379 78%20 238 (EC 1.6.5.3) chain NDUFA3 - human HFCBC16 559312 1330 WUblastx.64(Q9H743) CDNA: FLJ21394 FIS, Q9H743 55% 998 792 CLONE COL03536. HFCBT29654842 1334 WUblastx.64 (Q9H9H1) CDNA FLJ12756 FIS, Q9H9H1 73% 80 280CLONE NT2RP2001295, WEAKLY SIMILAR TO ZIN HFCDN13 722221 1336WUblastx.64 (Q9P0T7) HSPC186 Q9P0T7 90% 2 187 (HYPOTHETICAL 20.6 KDAPROTEIN). HFCDT67 598900 1337 WUblastx.64 (Q9H0N3) HYPOTHETICAL 107.1KDA Q9H0N3 82% 9 455 PROTEIN. 77% 845 910 45% 373 438 67% 498 902HFCDY36 834512 1338 WUblastx.64 catalase (EC 1.11.1.6) -pir|I40767|I40767 93% 279 190 Campylobacter jejuni HFCEC45 847384 1339WUblastx.64 (Q9D3Q4) 5033428A16RIK Q9D3Q4 98% 68 349 PROTEIN. HFCET43596813 1340 WUblastx.64 (Q9Z1M7) Q9Z1M7 100% 7 144ACETYLGLUCOSAMINYLTRANSFERASE- LIKE PROTEIN. HFEAG55 838142 1341WUblastx.64 (Q9EP97) SENTRIN/SUMO- Q9EP97 100% 12 200 SPECIFIC PROTEASE(SMT3 ISOPEPTIDASE 1). HFEAU63 790190 1342 WUblastx.64 ISOFORM EYA1B OFQ99502 sp_vs|Q99502- 90% 2180 2028 01|Q99502 HFEBA88 684297 1343WUblastx.64 (BAB55210) CDNA FLJ14675 fis, BAB55210 100% 205 297 cloneNT2RP2003952, w 44% 70 327 HFEBO15 831772 1345 WUblastx.64 (Q9HC46)HYPOTHETICAL 42.8 KDA Q9HC46 85% 226 477 PROTEIN. 53% 150 332 51% 2 298HFEBO17 852218 1346 WUblastx.64 (BAB55130) CDNA FLJ14559 fis, BAB55130100% 523 624 clone NT2RM2001998. 91% 606 809 HFFAE46 654843 1347WUblastx.64 (O14597) NON-FUNCTIONAL O14597 100% 608 658 FOLATE BINDINGPROTEIN. 96% 703 801 78% 386 442 58% 602 649 57% 402 632 HFFAH01 8434381348 WUblastx.64 hypothetical protein pir|T43460|T43460 91% 510 241DKFZp434P1721.1 - human 98% 259 11 (fragment) 95% 818 513 HFFAL70 8275701349 WUblastx.64 (AAH07384) Unknown (protein for AAH07384 84% 921 466IMAGE: 3677194) (Fra HFFAV61 664486 1350 WUblastx.64 (BAA92711) Adaptorprotein BAA92711 100% 1555 1184 p130Cas. 50% 577 536 HFGAN63 708053 1353WUblastx.64 (Q9D4E9) 4932701A20RIK Q9D4E9 34% 159 542 PROTEIN. 52% 561617 HFIAB78 581054 1355 WUblastx.64 (Q9UKA1) F-BOX PROTEIN FBL5 Q9UKA1100% 672 872 (FRAGMENT). 100% 14 667 58% 608 658 32% 461 661 36% 690 836HFIIK29 843587 1360 WUblastx.64 (Q9H705) CDNA: FLJ21611 FIS, Q9H705 94%48 218 CLONE COL07344. HFIIK29 852308 1361 WUblastx.64 (Q9H705) CDNA:FLJ21611 FIS, Q9H705 94% 48 218 CLONE COL07344. HFIIK29 873681 1362WUblastx.64 (Q9H705) CDNA: FLJ21611 FIS, Q9H705 94% 48 218 CLONECOL07344. HFIIK29 885007 1363 WUblastx.64 (Q9H705) CDNA: FLJ21611 FIS,Q9H705 94% 48 218 CLONE COL07344. HFIIZ61 855939 1366 WUblastx.64(Q62786) PROSTAGLANDIN F2- FPRP_RAT 92% 35 229 ALPHA RECEPTOR REGULATORYPROTEIN HFIUT21 794323 1372 WUblastx.64 (AAH07934) DKFZP434A043 AAH07934100% 6 320 protein. HFIXC39 683053 1374 WUblastx.64 hypothetical protein1 - rat (fragment) pir|S33477|S33477 36% 1816 1541 HFIXC69 704080 1375WUblastx.64 (Q9NRX3) NADH: UBIQUINONE Q9NRX3 87% 32 292 OXIDOREDUCTASEMLRQ SUBUNIT HOMOLOG. HFIXE39 844408 1376 WUblastx.64 (CAC18649)Lipoyl-containing CAC18649 100% 1394 1651 component X precursor. HFIYP15688044 1377 WUblastx.64 (Q9H324) ZINC Q9H324 49% 430 1074METALLOENDOPEPTIDASE 35% 406 915 (FRAGMENT). 31% 553 1110 36% 712 96633% 577 738 34% 481 558 HFKBC47 847076 1383 WUblastx.64 (O95302)FK506-BINDING O95302 99% 1177 323 PROTEIN (FRAGMENT). 54% 1174 404 47%997 323 HFKDX53 731867 1384 WUblastx.64 (Q9BTV6) UNKNOWN (PROTEIN Q9BTV6100% 407 763 FOR IMAGE: 3502107) 65% 204 371 (FRAGMENT). 100% 766 1296HFKEB14 709663 1385 WUblastx.64 (Q9NVY4) CDNA FLJ10436 FIS, Q9NVY4 97% 8127 CLONE NT2RP1000574, HIGHLY SIMILAR TO HOM HFKEU17 815554 1389WUblastx.64 (AAH00465) Growth arrest and DNA- AAH00465 97% 226 330damage-inducible, 86% 473 784 HFKEV77 850678 1390 WUblastx.64hypothetical protein pir|T14797|T14797 89% 238 567 DKFZp564B167.1 -human HFKFI15 775846 1391 WUblastx.64 (Q12948) FORKHEAD BOX FXC1_HUMAN100% 2 166 PROTEIN C1 (FORKHEAD- RELATED PROTEIN HFKFK49 847077 1393WUblastx.64 (Q9UHR0) MAP KINASE- Q9UHR0 100% 277 366 INTERACTING KINASE.HFOXD49 844524 1398 WUblastx.64 (O15194) YA22 PROTEIN (HYA22). O1519499% 7 435 HFOXE28 847385 1399 WUblastx.64 (Q9H0E0) HYPOTHETICAL 13.4 KDAQ9H0E0 47% 1011 1286 PROTEIN. 39% 135 476 34% 360 671 60% 837 881HFOYR54 743196 1403 WUblastx.64 (O00566) U3 SMALL NUCLEOLAR MP10_HUMAN78% 118 1365 RIBONUCLEOPROTEIN PROTEIN 63% 136 168 MPP10 HFPBQ55 6081711409 WUblastx.64 (Q24333) ELASTIN LIKE PROTEIN Q24333 100% 45 116(FRAGMENT). HFPCM32 608215 1411 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS,Q9H743 48% 719 441 CLONE COL03536. HFPCU47 741049 1414 WUblastx.64(Q9H728) CDNA: FLJ21463 FIS, Q9H728 59% 1645 1580 CLONE COL04765. 58%1598 1356 HFPCY66 825718 1415 WUblastx.64 (Q9H387) PRO2550. Q9H387 72%1371 1252 72% 1555 1424 HFPDC65 839208 1416 WUblastx.64 (Q9H5G8) CDNA:FLJ23451 FIS, Q9H5G8 100% 72 605 CLONE HSI06456. HFPDE42 844402 1417WUblastx.64 (Q99PQ3) TRIPARTITE MOTIF Q99PQ3 97% 3 218 PROTEIN TRIM9(FRAGMENT). HFPDP70 745433 1420 WUblastx.64 (Q9H919) CDNA FLJ13078 FIS,Q9H919 83% 937 990 CLONE NT2RP3002002. 88% 879 905 58% 980 1096 HFPDX08746379 1422 WUblastx.64 (Q9H9Y3) CDNA FLJ12474 FIS, Q9H9Y3 100% 3 311CLONE NT2RM1000927. HFPEP69 835459 1423 WUblastx.64 (Q9P0X1)LIPOPOLYSACCHARIDE Q9P0X1 96% 654 749 SPECIFIC RESPONSE-5 PROTEIN(FRAGMENT). HFRAU40 701986 1424 WUblastx.64 hypothetical protein 3 -human pir|E41925|E41925 34% 228 109 57% 511 428 45% 428 252 HFSAY91828067 1426 WUblastx.64 hypothetical protein pir|T46933|T46933 100% 12801197 DKFZp434M035.1 - human 92% 1096 437 HFSBC10 638315 1427 WUblastx.64(O95025) SEMAPHORIN 3D SM3D_HUMAN 82% 1437 532 PRECURSOR. 82% 626 23154% 742 443 100% 234 67 HFSBE94 600398 1428 WUblastx.64 (Q9P195)PRO1722. Q9P195 75% 705 610 73% 853 695 HFTAN11 638316 1429 WUblastx.64(Q9H387) PRO2550. Q9H387 54% 676 614 82% 771 667 68% 537 490 83% 617 489HFTBL17 844488 1434 WUblastx.64 (Q14288) HYPOTHETICAL Q14288 95% 967 710PROTEIN (FRAGMENT). HFTBL17 863152 1435 WUblastx.64 (Q14288)HYPOTHETICAL Q14288 95% 969 712 PROTEIN (FRAGMENT). HFTCI85 664487 1437WUblastx.64 (O60448) NEURONAL THREAD O60448 63% 1140 1075 PROTEINAD7C-NTP. 92% 1070 1032 38% 1139 1032 67% 1285 1130 59% 1067 1002 33%877 707 65% 1275 1129 77% 1283 1257 72% 1276 1019 HFTCJ32 604911 1438WUblastx.64 (Q9H387) PRO2550. Q9H387 59% 669 586 71% 889 689 HFTCO17844354 1439 WUblastx.64 (Q9QY01) SERINE/THREONINE Q9QY01 83% 1 231KINASE UNC51.2. 95% 216 611 HFTCW07 604987 1440 WUblastx.64 (Q9H5R3)CDNA: FLJ23147 FIS, Q9H5R3 75% 798 589 CLONE LNG09295. HFTDF32 6003601441 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 73% 1017 1310 CLONECOL04765. HFTDF79 827459 1442 WUblastx.64 hypothetical protein XF0051pir|G82853|G82853 40% 873 691 [imported]- Xylella fastidiosa (strain 32%872 627 9a5c) 51% 1202 1113 42% 813 589 32% 961 716 28% 792 424 62% 11841113 62% 1184 1113 42% 873 619 HFTDK11 837382 1443 WUblastx.64 (Q9Y6D7)ES18 (FRAGMENT). Q9Y6D7 100% 2 67 100% 558 650 63% 97 618 HFTDU08 8257151444 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 70% 885 775 CLONEKAIA0536. HFVGK67 569778 1445 WUblastx.64 (Q9H387) PRO2550. Q9H387 83%1269 985 HFVHD38 826709 1446 WUblastx.64 SHORT ISOFORM OF O00339sp_vs|O00339- 98% 2163 550 01|O00339 56% 2163 1387 50% 2163 1387 49%2163 1387 48% 2142 1387 40% 1386 820 HFVIC33 799524 1448 HMMER PFAM:Enoyl-CoA PF00378 34.7 462 680 2.1.1 hydratase/isomerase familyWUblastx.64 (Q9NTX5) DJ351K20.2.1 (NOVEL Q9NTX5 96% 694 975 ENOYLCOA/ACYL COA 99% 72 716 HYDRATASE/DEHYDROGENA HFXAK32 638319 1449WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 40% 1403 1104 PROTEIN.HFXAK59 831141 1450 WUblastx.64 (Q9BTC8) SIMILAR TO Q9BTC8 95% 1537 431METASTASIS ASSOCIATED 1. HFXBM52 737672 1453 WUblastx.64 (Q9HA67) CDNAFLJ12155 FIS, Q9HA67 80% 708 631 CLONE MAMMA1000472. 50% 123 64 68% 569465 HFXBV67 748230 1455 WUblastx.64 hypothetical protein (L1H 3′region) - pir|B34087|B34087 52% 1618 1319 human HFXCI42 606806 1458WUblastx.64 (Q9GMI7) HYPOTHETICAL 9.0 KDA Q9GMI7 43% 542 297 PROTEIN.72% 534 406 HFXCL59 825713 1459 WUblastx.64 (Q9NSI6) WD-REPEAT PROTEIN 9WDR9_HUMAN 90% 1008 397 (FRAGMENT). 76% 53 3 35% 1002 385 28% 993 60424% 960 556 29% 349 182 100% 367 182 88% 180 154 HFXCS53 828903 1462WUblastx.64 (Q9H8H0) CDNA FLJ13640 FIS, Q9H8H0 99% 1107 442 CLONEPLACE1011221. HFXDB37 569805 1463 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9KDA Q9GMX5 58% 1116 1208 PROTEIN. 57% 991 1131 HFXDL76 821571 1466WUblastx.64 probable pol polyprotein-related pir|S21348|S21348 63% 18111746 protein 4 - rat 48% 1520 1446 64% 1740 1519 HFXDP44 590269 1469WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 64% 531 761 CLONEKAT08285. 50% 918 1115 88% 745 825 36% 1005 1103 30% 660 779 HFXDR08621342 1470 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 64% 506700 PROTEIN. HFXDR28 621300 1471 WUblastx.64 (Q9H5R3) CDNA: FLJ23147FIS, Q9H5R3 68% 652 717 CLONE LNG09295. 70% 501 653 HFXDR28 873859 1472WUblastx.64 (Q9H5X2) CDNA: FLJ22865 FIS, Q9H5X2 98% 853 314 CLONEKAT02171. HFXDR47 846477 1473 WUblastx.64 (Q9H387) PRO2550. Q9H387 100%977 957 92% 1051 1010 65% 957 733 HFXDZ03 846323 1474 WUblastx.64(Q9UN78) HYPOTHETICAL 40.1 KDA Q9UN78 32% 1065 739 PROTEIN. 52% 528 38524% 1161 877 39% 757 521 HFXEE88 838822 1476 WUblastx.64 (Q9NX17) CDNAFLJ20489 FIS, Q9NX17 56% 1310 1116 CLONE KAT08285. HFXGR32 534607 1477WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, Q9HA67 57% 24 272 CLONEMAMMA1000472. HFXGT51 638174 1478 WUblastx.64 (Q9NX85) CDNA FLJ20378FIS, Q9NX85 74% 1126 989 CLONE KAIA0536. 78% 1232 1107 HFXHI33 8742551481 WUblastx.64 (Q9HBS7) HYPOTHETICAL 14.2 KDA Q9HBS7 66% 1535 1278PROTEIN. HFXHL21 581363 1482 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDAQ9BGW3 56% 1441 1373 PROTEIN. 64% 1601 1443 HFXHM93 858720 1485WUblastx.64 (AAK55521) PRO0764. AAK55521 66% 803 1027 HFXHN89 7861961486 WUblastx.64 (O60448) NEURONAL THREAD O60448 61% 1063 1218 PROTEINAD7C-NTP. 59% 1208 1273 65% 1072 1332 HFXJB21 743165 1487 WUblastx.64(Q9H728) CDNA: FLJ21463 FIS, Q9H728 73% 1269 1003 CLONE COL04765.HFXJN93 596815 1488 WUblastx.64 (Q9D4B1) 4933405A16RIK Q9D4B1 97% 501298 PROTEIN. HFXJS15 800866 1489 WUblastx.64 (Q9ESN6) NEURAL ACTIVITY-Q9ESN6 97% 1 447 RELATED RING FINGER PROTEIN 32% 37 438 (TRIPARTITE MOTI33% 10 435 31% 10 516 HFXJT53 823591 1490 WUblastx.64 (AAL50053)Viperin. AAL50053 94% 111 1193 HFXKL60 895307 1492 WUblastx.64 (Q9H3C0)PRO0898. Q9H3C0 37% 1749 1889 67% 1865 2029 HFXLG08 885514 1493WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 60% 1303 1067 PROTEIN.HFXLK91 827288 1494 WUblastx.64 (Q9NWT2) CDNA FLJ20623 FIS, Q9NWT2 87% 3827 CLONE KAT04793. HGBBR29 823106 1497 WUblastx.64 (O43592) EXPORTIN T.O43592 100% 183 1118 HGBDV35 581058 1499 WUblastx.64 (AAK53702) ADMP.AAK53702 42% 91 252 HGBHE23 832303 1502 WUblastx.64 hypothetical proteinpir|T12479|T12479 86% 24 455 DKFZp564N1362.1 - human (fragment) HGBHI15608170 1503 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 63% 663565 PROTEIN. 65% 559 380 HGLAG32 668271 1505 WUblastx.64 (Q9BRZ3)UNKNOWN (PROTEIN Q9BRZ3 66% 2 154 FOR MGC: 2724). HGLAH86 603525 1507WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 55% 824 618 CLONEKAT08285. HHEBP28 775744 1517 WUblastx.64 (Q9BRL7) SIMILAR TO VESICLEQ9BRL7 100% 3 233 TRAFFICKING PROTEIN. HHECR10 621371 1519 WUblastx.64(Q9H7S6) CDNA FLJ14310 FIS, Q9H7S6 64% 972 766 CLONE PLACE3000271.HHEMC55 566796 1520 WUblastx.64 (O60448) NEURONAL THREAD O60448 64% 605417 PROTEIN AD7C-NTP. 42% 659 417 63% 1063 896 48% 912 808 41% 575 40547% 1063 965 40% 1017 781 42% 976 878 61% 1060 827 32% 1063 812 50% 896771 80% 349 320 65% 656 597 40% 606 325 43% 516 343 45% 941 885 65% 606445 HHEMP35 821328 1523 WUblastx.64 (Q9Y6X2) PROTEIN INHIBITOR OF Q9Y6X293% 302 931 ACTIVATIED STAT3 (PROTEIN 60% 75 308 INHIBITOR OF HHEMZ08840026 1524 WUblastx.64 (Q9NZ80) UNCHARACTERIZED Q9NZ80 77% 845 1351BONE MARROW PROTEIN BM042. HHENR74 825671 1527 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 70% 1005 1085 CLONE COL04765. 77% 811 876 76%878 1003 HHENY07 638321 1529 WUblastx.64 (O00311) CELL DIVISION CYCLECDC7_HUMAN 88% 8 136 7-RELATED PROTEIN KINASE (EC 2 98% 121 744 HHEOK77841099 1530 WUblastx.64 (Q9Z1W6) P80 (FRAGMENT). Q9Z1W6 76% 238 276 87%942 1127 23% 510 764 80% 315 977 HHEPE72 621254 1531 WUblastx.64(Q9H728) CDNA: FLJ21463 FIS, Q9H728 53% 1015 749 CLONE COL04765. HHEPE81840614 1532 WUblastx.64 (O95373) RANBP7/IMPORTIN 7. O95373 86% 3 389HHEQY60 799535 1535 WUblastx.64 (O60448) NEURONAL THREAD O60448 68% 703566 PROTEIN AD7C-NTP. 62% 731 555 68% 568 503 47% 570 502 58% 489 43965% 731 429 HHFEB79 1300768 1541 WUblastx.64 (Q92545) RW1 PROTEINRW1_HUMAN 74% 708 2387 (FRAGMENT). 80% 6 590 32% 1984 2148 HHFEB79863749 3107 WUblastx.64 Similar to a C. elegans protein encodeddbj|BAA13387.1| 69% 1303 2400 in cosmid C27F2 (U40419) [Homo 80% 6011185 sapiens] HHFEN34 701992 1543 WUblastx.64 (Q9HAD8) CDNA FLJ11786FIS, Q9HAD8 63% 709 644 CLONE HEMBA1006036. 57% 942 691 HHFFZ01 8473881544 WUblastx.64 (Q9H6Y7) CDNA: FLJ21676 FIS, Q9H6Y7 89% 835 1080 CLONECOL09164. 91% 1077 1763 HHFGI71 663531 1545 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 75% 1174 1272 PROTEIN. 67% 1424 1269HHFGJ54 731870 1546 WUblastx.64 (Q9H906) CDNA FLJ13099 FIS, Q9H906 99%1232 1645 CLONE NT2RP3002248. 96% 510 1259 HHFGL38 833063 1547WUblastx.64 (Q9H387) PRO2550. Q9H387 53% 2764 2465 HHFGZ23 721653 1549WUblastx.64 hypothetical protein 3 - human pir|E41925|E41925 64% 9781136 HHFHM47 638181 1551 WUblastx.64 (O60448) NEURONAL THREAD O60448 76%680 618 PROTEIN AD7C-NTP. 40% 804 670 65% 802 671 84% 611 573 72% 681616 60% 77 3 62% 838 557 HHGAA76 767745 1552 WUblastx.64 (Q14288)HYPOTHETICAL Q14288 49% 1301 870 PROTEIN (FRAGMENT). 69% 499 431 68% 593 74% 1455 1294 66% 888 505 HHGAD46 812646 1553 WUblastx.64 (Q9UGT4)BK65A6.2 (NOVEL Q9UGT4 85% 148 783 SUSHI DOMAIN (SCR REPEAT) 67% 3 203CONTAINING PROTEIN HHGBC21 840455 1555 WUblastx.64 (Q9H743) CDNA:FLJ21394 FIS, Q9H743 54% 1118 858 CLONE COL03536. HHGBW55 638183 1559WUblastx.64 hypothetical protein [imported] - pir|T50835|T50835 97% 3143 human HHGDR05 610266 1564 WUblastx.64 (Q9HAD8) CDNA FLJ11786 FIS,Q9HAD8 63% 821 690 CLONE HEMBA1006036. HHGDR92 840454 1565 WUblastx.64(Q9Y512) PROTEIN CGI-51. CG51_HUMAN 99% 10 1104 HHGDS56 663379 1566WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 57% 1318 1187 CLONEKAIA0536. 62% 1476 1309 HHGDW65 825652 1567 WUblastx.64 (Q9GMX5)HYPOTHETICAL 12.9 KDA Q9GMX5 56% 463 726 PROTEIN. HHPDE28 877640 1571WUblastx.64 (Q9H620) CDNA: FLJ22673 FIS, Q9H620 98% 393 596 CLONEHSI10503. HHPEB61 658693 1575 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS,Q9H743 50% 777 935 CLONE COL03536. 54% 622 804 HHPFP26 753269 1576WUblastx.64 (Q9BQG8) HYPOTHETICAL 32.5 KDA Q9BQG8 100% 906 1742 PROTEIN.HHPFS11 570807 1577 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 50%402 587 CLONE COL04765. HHPFS18 829347 1579 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 75% 2558 2427 CLONE COL04765. HHPGH34 535780 1580WUblastx.64 (Q9BVD9) UNKNOWN (PROTEIN Q9BVD9 68% 1019 972 FOR MGC:5149). 64% 835 794 68% 963 850 HHPGU87 658694 1582 WUblastx.64 SHORTISOFORM OF O60658 sp_vs|O60658- 100% 1050 1274 01|O60658 HHPSE55 7355621585 WUblastx.64 (Q9CQ15) 0610011N22RIK Q9CQ15 79% 67 846 PROTEIN (RIKENCDNA 0610011N22 GENE). HHPSF70 709665 1586 WUblastx.64 (AAH18471)Similar to nitrogen AAH18471 81% 1 96 fixation gene 1 (S. HHPSH74 6381851587 WUblastx.64 hypothetical protein DKFZp566E044.1 - pir|T46284|T4628472% 323 1339 human 99% 10 321 54% 10 321 53% 323 571 20% 752 1030 87%1272 1730 HHPTF26 857654 1590 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDAQ9BGW3 66% 1006 752 PROTEIN. HHSAE74 839473 1592 WUblastx.64 (Q9P1J1)PRO1546. Q9P1J1 89% 451 365 87% 588 442 HHSAG62 847392 1593 WUblastx.64(Q9H876) CDNA FLJ13898 FIS, Q9H876 99% 2 460 CLONE THYRO1001738, WEAKLY99% 600 1052 SIMILAR TO TUB 100% 533 604 HHSBJ92 838604 1595 WUblastx.64(Q9BTM2) SIMILAR TO RIKEN Q9BTM2 100% 509 718 CDNA 1300006O23 GENE(FRAGMENT). HHSDB43 812510 1600 HMMER PFAM: Zinc finger, C2H2 typePF00096 117.4 877 945 2.1.1 WUblastx.64 hypothetical proteinpir|T42688|T42688 92% 25 1344 DKFZp434H0127.1 - human (fragment) HHSDL07899430 1601 WUblastx.64 (Q9UJH9) C380A1.2.1 (NOVEL Q9UJH9 85% 9 317PROTEIN (ISOFORM 1)) (UNKNOWN) (PROTEIN FO HHSDX07 847393 1602WUblastx.64 (Q9H9W2) CDNA FLJ12510 FIS, Q9H9W2 86% 3 512 CLONENT2RM2001723. 79% 434 1066 HHSFF54 836149 1603 WUblastx.64 (Q9BS18)UNKNOWN (PROTEIN Q9BS18 100% 129 350 FOR MGC: 12537). HIABC70 8386051607 WUblastx.64 (Q9NPJ9) APOLIPOPROTEIN B48 Q9NPJ9 77% 15 851 RECEPTOR.100% 1047 1160 34% 522 821 25% 303 842 24% 306 818 24% 312 839 HIBCO70853360 1609 HMMER PFAM: Myelin proteolipid protein PF01275 32.3 127 1922.1.1 (PLP or lipophilin) WUblastx.64 (Q99NH0) GENE TRAP ANKYRIN Q99NH095% 176 1564 REPEAT CONTAINING PROTEIN. 38% 410 1414 39% 413 1408 37%419 1411 39% 413 1408 38% 410 1360 37% 443 1441 38% 425 1420 37% 6081411 38% 407 1141 33% 887 1411 HIBDA41 603909 1611 WUblastx.64 (Q9H387)PRO2550. Q9H387 80% 404 697 HIBEC45 822854 1612 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 63% 1023 1283 PROTEIN. HILBW03 841377 1613WUblastx.64 (Q9NVS4) CDNA FLJ10546 FIS, Q9NVS4 97% 705 1163 CLONENT2RP2001721. HISAE16 845233 1614 WUblastx.64 (Q9H728) CDNA: FLJ21463FIS, Q9H728 85% 7 90 CLONE COL04765. HISAG53 843902 1615 WUblastx.64(BAB55426) CDNA FLJ14972 fis, BAB55426 100% 84 122 clone THYRO1000715.83% 952 1614 78% 127 993 HISAN63 797658 1616 WUblastx.64 (O00363)PUTATIVE P150. O00363 33% 1609 1427 29% 1299 1045 59% 1454 1392 35% 716384 HISAT78 840961 1617 WUblastx.64 (Q9NUD5) DJ1103G7.7 (PUTATIVE Q9NUD566% 155 280 NOVEL PROTEIN). 96% 13 108 29% 594 767 100% 114 194 32% 591785 50% 538 567 100% 576 743 98% 280 567 HISBA38 561711 1618 WUblastx.64(Q9H387) PRO2550. Q9H387 53% 919 836 53% 996 907 51% 842 687 HISBB66839808 1619 WUblastx.64 (O95627) POTENTIAL O95627 88% 2 451TRANSCRIPTIONAL REPRESSOR NOT4HP. HISEJ52 886777 1623 WUblastx.64(Q9Y6J0) CALCINEURIN-BINDING CABI_HUMAN 94% 480 1697 PROTEIN CABIN 1(CALCINEURIN I HJABC58 753272 1624 WUblastx.64 (Q9H743) CDNA: FLJ21394FIS, Q9H743 68% 993 928 CLONE COL03536. 73% 1186 998 HJABS31 825607 1627WUblastx.64 (AAG49400) Ring-H2 protein. AAG49400 90% 1 1221 HJACE25835517 1629 WUblastx.64 (O75921) RNA POLYMERASE II O75921 95% 381 662TERMINATION FACTOR. 91% 64 390 HJACK21 664506 1630 WUblastx.64 (Q9CYB5)5730552M22RIK Q9CYB5 98% 530 1123 PROTEIN. HJBCG74 839361 1631WUblastx.64 (Q9UNW1) MULTIPLE INOSITOL Q9UNW1 88% 33 560 POLYPHOSPHATE99% 560 1492 PHOSPHATASE. HJBCO21 695727 1632 WUblastx.64 (Q9Y6E5)HSPC024-ISO. Q9Y6E5 84% 9 482 HJBCQ40 831119 1633 WUblastx.64 (BAB55245)CDNA FLJ14722 fis, BAB55245 84% 58 1068 clone NT2RP3001621. HJBDM36773168 1634 WUblastx.64 (O15498) SNARE PROTEIN YKT6. O15498 92% 127 720HJMAZ60 844796 1637 WUblastx.64 (Q9D9R1) ADULT MALE TESTIS Q9D9R1 87%482 1054 CDNA, RIKEN FULL-LENGTH 88% 14 484 ENRICHED LIBRARY, HJMBB20824264 1638 WUblastx.64 ISOFORM GAC OF O94925 sp_vs|O94925- 99% 3 52702|O94925 HJMBB20 842673 1639 WUblastx.64 ISOFORM GAC OF O94925sp_vs|O94925- 100% 4 1461 02|O94925 HJMBB20 844890 1640 WUblastx.64ISOFORM GAC OF O94925 sp_vs|O94925- 100% 4 1461 02|O94925 HJMBK59 6644901641 WUblastx.64 (O75935) DYNACTIN SUBUNIT. O75935 100% 2 286 HJMBP01638190 1642 WUblastx.64 (AAH00573) HSPC163 protein. AAH00573 100% 13 174HJPAF69 589794 1646 WUblastx.64 (Q9H387) PRO2550. Q9H387 77% 439 531 73%278 424 HJPAQ19 566832 1647 WUblastx.64 hypothetical proteinpir|T08694|T08694 78% 9 869 DKFZp564O092.1 - human (fragment) HJPAZ35845379 1648 WUblastx.64 (Q9Y262) HSPC025. Q9Y262 95% 126 1745 HJPBI77602875 1649 WUblastx.64 (Q9V756) CG10155 PROTEIN. Q9V756 42% 16 249HJPBN96 610087 1650 WUblastx.64 (Q9NX09) CDNA FLJ20500 FIS, Q9NX09 100%106 288 CLONE KAT09159. 100% 70 108 HJPBU47 824063 1651 WUblastx.64(Q9NPM0) 8D6 ANTIGEN Q9NPM0 100% 240 377 (FRAGMENT). 77% 315 380 73% 261329 80% 329 844 HJPDK61 844034 1654 WUblastx.64 (Q9V7R7) CG8311 PROTEIN.Q9V7R7 41% 466 1194 HKABI53 805966 1655 WUblastx.64 (Q9BUP3)TAT-INTERACTING Q9BUP3 93% 126 212 PROTEIN (30 KD). 99% 212 778 HKABN63566840 1656 WUblastx.64 (Q9BRZ8) SIMILAR TO RIKEN Q9BRZ8 85% 40 306 CDNA1810009K13 GENE. 98% 263 700 HKACA25 824087 1657 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 64% 1493 1543 PROTEIN. 66% 1276 1488HKACO64 897591 1658 WUblastx.64 (Q9P195) PRO1722. Q9P195 61% 694 593 58%930 748 HKACX90 604042 1660 WUblastx.64 (Q9CZH5) 2700094L05RIK Q9CZH569% 13 510 PROTEIN. HKADI27 1028177 1661 WUblastx.64 (O35390)ENDO-ALPHA-D- O35390 65% 302 562 MANNOSIDASE. 51% 531 602 87% 574 1512HKADN26 802131 1662 WUblastx.64 (Q24333) ELASTIN LIKE PROTEIN Q24333 48%57 263 (FRAGMENT). HKADT55 668243 1664 WUblastx.64 (Q9CS80)5730420G12RIK PROTEIN Q9CS80 97% 454 708 (FRAGMENT). 93% 13 57 HKAEK58695729 1665 HMMER PFAM: Acyl-CoA dehydrogenase PF00441 449.8 160 12692.1.1 WUblastx.64 (Q9UKU7) ACYL-COENZYME A Q9UKU7 100% 39 113DEHYDROGENASE-8. 99% 112 1284 HKAEK72 840457 1666 HMMER PFAM: Sugar (andother) transporter PF00083 70.8 270 575 2.1.1 WUblastx.64 (Q9UGQ3) SUGARTRANSPORTER Q9UGQ3 99% 9 602 (GLUCOSE TRANSPORTER 9). HKAFQ41 8472811668 WUblastx.64 (O94771) TRANSCRIPTION O94771 84% 36 896 FACTOR-LIKE 5.HKAHH71 846826 1669 WUblastx.64 (Q9VAA6) CG7950 PROTEIN. Q9VAA6 57% 31348 HKAKU90 838608 1671 WUblastx.64 (Q9H2T6) ANTIGEN ART1/P17. Q9H2T685% 19 1230 HKFAA15 753275 1673 WUblastx.64 (Q9P195) PRO1722. Q9P195 67%1748 1593 76% 1605 1465 HKGAJ81 581063 1676 WUblastx.64 (Q9H387)PRO2550. Q9H387 81% 445 335 48% 1240 1166 70% 620 429 HKGAK45 8090931677 WUblastx.64 (Q9H387) PRO2550. Q9H387 63% 1946 1815 68% 2088 1945HKGAP57 841627 1679 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 54%770 639 CLONE KAIA0536. 72% 907 767 HKGAW41 858745 1680 WUblastx.64(Q9H728) CDNA: FLJ21463 FIS, Q9H728 68% 1458 1327 CLONE COL04765. 71%1622 1431 HKGBA21 822870 1681 WUblastx.64 (O00367) L1 ELEMENT L1.19 P40O00367 55% 1697 1783 PROTEIN. 30% 810 1064 50% 1279 1731 HKGBC33 8233681682 WUblastx.64 (Q9UI50) PRO0657 (FRAGMENT). Q9UI50 76% 783 1001HKGBC73 608169 1683 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV854% 74 9 PROTEIN. 78% 133 77 HKGBF61 658697 1684 WUblastx.64 (AAK55521)PRO0764. AAK55521 70% 978 919 39% 1700 1587 59% 138 73 70% 1171 980HKGBH54 588482 1685 WUblastx.64 (Q9UHT1) PRO1902 PROTEIN. Q9UHT1 61%2206 2114 43% 1994 1884 54% 2135 1959 HKGBP52 899282 1686 WUblastx.64(Q9NX85) CDNA FLJ20378 FIS, Q9NX85 68% 1562 1440 CLONE KAIA0536. 76%1726 1556 HKGCE23 564825 1687 WUblastx.64 (Q9D445) 4933414E04RIK Q9D44560% 1456 1749 PROTEIN. HKGCE62 638200 1688 WUblastx.64 (Q9UHT1) PRO1902PROTEIN. Q9UHT1 63% 995 897 61% 1131 985 HKGCK41 559327 1689 WUblastx.64(Q9NQ89) MIB001 PROTEIN. Q9NQ89 93% 20 583 HKGCK41 795256 1690WUblastx.64 (Q9NQ89) MIB001 PROTEIN. Q9NQ89 93% 31 591 HKGDA95 5810641693 WUblastx.64 (Q9BYC7) MITOCHONDRIAL Q9BYC7 98% 77 313 RIBOSOMALPROTEIN BMRP36A. 98% 618 782 82% 428 625 HKGDO12 857225 1694 WUblastx.64(O60448) NEURONAL THREAD O60448 55% 1223 1170 PROTEIN AD7C-NTP. 72% 14291277 57% 1437 1222 48% 1218 1129 56% 1289 1146 79% 1441 1223 HKIME53636982 1695 WUblastx.64 (Q9H3S2) HCCA2 PROTEIN. Q9H3S2 100% 4 30 100% 2970 89% 63 446 HKIMG23 738671 1696 WUblastx.64 (O75896) FUS1 PROTEIN.FUS1_HUMAN 76% 217 255 100% 131 172 100% 246 458 HKMLF77 604743 1704WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 91% 673 638 CLONEKAIA0536. 88% 737 684 52% 627 457 HKMLM32 826523 1705 WUblastx.64(Q9P0E3) HSPC093 (FRAGMENT). Q9P0E3 57% 861 1001 HKMLR17 847432 1706HMMER PFAM: CUB domain PF00431 145 425 760 2.1.1 WUblastx.64 (Q9UKZ9)PROCOLLAGEN C- Q9UKZ9 94% 8 1210 TERMINAL PROTEINASE ENHANCER PROTEIN 2.HKMLT89 826167 1707 WUblastx.64 (Q9HD86) NAG18. Q9HD86 87% 1141 1233HKMLV05 663924 1708 WUblastx.64 (Q9H387) PRO2550. Q9H387 81% 1559 1290HKMLV25 695731 1709 WUblastx.64 (Q9BT42) SIMILAR TO LR8 Q9BT42 97% 328474 PROTEIN. 40% 266 340 99% 2 334 HKMMD91 847394 1712 WUblastx.64(AAH07729) Similar to RIKEN cDNA AAH07729 100% 1150 752 2810021O14 gene.HKMMP90 746876 1713 WUblastx.64 (O40947) ORF 73. O40947 30% 237 398 28%240 443 30% 210 317 24% 1054 1569 25% 1054 1659 24% 1054 1659 25% 10541659 25% 1060 1662 23% 1054 1677 HKPAC10 527238 1715 WUblastx.64(Q9HAD8) CDNA FLJ11786 FIS, Q9HAD8 47% 970 677 CLONE HEMBA1006036.HKPAC50 830367 1716 WUblastx.64 (O95139) NADH-UBIQUINONE NB7M_HUMAN 61%106 324 OXIDOREDUCTASE B17 SUBUNIT (EC 1.6 HKTAC18 831292 1718WUblastx.64 (Q9Y5W8) SORTING NEXIN 13 SNXD_HUMAN 88% 3 53 (FRAGMENT).96% 38 400 HL1SA89 839594 1719 WUblastx.64 (Q9Y399) MITOCHONDRIAL 28SQ9Y399 99% 63 641 RIBOSOMAL PROTEIN S2 (MRP- S2). HL2AB60 722226 1720WUblastx.64 SHORT ISOFORM OF Q9Y679 sp_vs|Q9Y679- 91% 64 1293 01|Q9Y679HL3AF32 753468 1722 WUblastx.64 (Q9CZ73) 2810049G06RIK Q9CZ73 76% 6 527PROTEIN. HLDAV70 623603 1723 WUblastx.64 (Q9UJW0) DYNACTIN P62 Q9UJW0100% 175 285 SUBUNIT (CDNA FLJ20292 FIS, CLONE HEP05374). HLDBL62 8994981724 WUblastx.64 (Q9NYC7) HEPATOCELLULAR Q9NYC7 78% 36 740CARCINOMA-ASSOCIATED ANTIGEN 112. HLDBV18 805684 1725 WUblastx.64(Q9H7D5) CDNA: FLJ21022 FIS, Q9H7D5 94% 284 1198 CLONE CAE06383. HLDBV54570813 1726 HMMER PFAM: Sec1 family PF00995 18.7 180 332 2.1.1 HLDNF18821599 1730 WUblastx.64 (Q9NWI8) CDNA FLJ20823 FIS, Q9NWI8 78% 17 583CLONE ADSE00282 (SIMILAR TO TRANSLOCASE O HLDNN84 612801 1731WUblastx.64 (Q9UHT1) PRO1902 PROTEIN. Q9UHT1 51% 751 849 59% 600 755HLDOD77 610208 1732 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX571% 513 617 PROTEIN. 62% 395 523 HLDOL74 812765 1733 WUblastx.64(Q9P0A2) HSPC279 (FRAGMENT). Q9P0A2 94% 57 671 HLDRU08 701995 1735WUblastx.64 (Q9NVD7) CDNA FLJ10793 FIS, Q9NVD7 99% 13 729 CLONENT2RP4000588 (ALPHA- PARVIN). HLDXF43 514022 1736 WUblastx.64cytochrome-c oxidase (EC 1.9.3.1) pir|A00472|OBHU2 52% 164 559 chainII - human mitochondrion HLEAA10 824265 1737 WUblastx.64 (Q13579)MARINER Q13579 85% 842 741 TRANSPOSASE. 77% 738 13 HLHAE14 865625 1739WUblastx.64 (Q9H7S6) CDNA FLJ14310 FIS, Q9H7S6 66% 1412 1528 CLONEPLACE3000271. 44% 935 1060 HLHAE14 886763 1740 WUblastx.64 (Q9H7S6) CDNAFLJ14310 FIS, Q9H7S6 66% 1412 1528 CLONE PLACE3000271. 44% 935 1060HLHBS54 837503 1741 WUblastx.64 (Q9NZV5) SELENOPROTEIN N SELN_HUMAN 92%1 1455 PRECURSOR. HLHCG24 847398 1744 WUblastx.64 (Q9BZE5) PGC-1 RELATEDCO- Q9BZE5 82% 10 615 ACTIVATOR. HLHCN51 836150 1746 WUblastx.64(Q9D1H8) 1110007K17RIK Q9D1H8 72% 1588 1514 PROTEIN. 48% 1514 1275HLHCT96 886178 1747 WUblastx.64 (Q9H6G8) CDNA: FLJ22294 FIS, Q9H6G8 90%1976 1917 CLONE HRC04426. 68% 2152 1955 HLHDJ05 841732 1750 WUblastx.64(Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 68% 812 708 PROTEIN. 66% 708 547HLHDL37 847399 1751 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 78%690 571 CLONE KAT08285. HLHDL69 883335 1752 WUblastx.64 (O09014)PEPTIDE/HISTIDINE O09014 88% 305 592 TRANSPORTER. 72% 598 1314 HLHDL69850691 1753 WUblastx.64 (O09014) PEPTIDE/HISTIDINE O09014 75% 305 340TRANSPORTER. 78% 330 1484 HLHDL69 843836 1754 WUblastx.64 (O09014)PEPTIDE/HISTIDINE O09014 75% 305 340 TRANSPORTER. 78% 330 1484 HLHDL69855906 1755 WUblastx.64 (O09014) PEPTIDE/HISTIDINE O09014 75% 305 340TRANSPORTER. 78% 330 1484 HLHDM38 566843 1756 WUblastx.64 hypotheticalprotein pir|T46471|T46471 45% 6 326 DKFZp434L0130.1 - human 39% 181 33961% 476 886 HLHDR92 692150 1757 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 77% 1252 1172 CLONE KAIA0536. 58% 1181 1095 HLHDY94 847121 1758WUblastx.64 (O00572) HYPOTHETICAL 43.0 KDA O00572 56% 637 876 PROTEIN.61% 18 752 HLHEI72 874180 1761 HMMER PFAM: Eukaryotic protein kinasePF00069 106.7 101 403 2.1.1 domain WUblastx.64 (Q9Y6S4) SIMILARITY IS TOQ9Y6S4 81% 589 621 SERINE/THREONINE-PROTEIN 97% 89 526 KINASE(FRAGMENT). HLHEX62 608285 1762 WUblastx.64 (Q9H387) PRO2550. Q9H387 70%1102 833 HLHFP09 805967 1764 WUblastx.64 ISOFORM 2 OF O95460sp_vs|O95460- 98% 3 881 01|O95460 38% 102 740 HLHGG78 638210 1765WUblastx.64 (O95989) DIPHOSPHOINOSITOL O95989 100% 10 291 POLYPHOSPHATEPHOSPHOHYDROLASE. HLHSQ35 570814 1767 WUblastx.64 (Q9JIX6) RNA BINDINGPROTEIN Q9JIX6 100% 671 712 NAPOR-3 (FRAGMENT). 87% 711 827 HLHTP55847322 1769 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 50% 320 433CLONE COL04765. 56% 462 635 HLIBD74 604914 1770 WUblastx.64 (Q9H797)CDNA: FLJ21128 FIS, Q9H797 98% 12 290 CLONE CAS06258. HLIBE41 7727621771 WUblastx.64 (Q9D0Q3) 1300007B24RIK Q9D0Q3 58% 71 409 PROTEIN.HLLAX64 827292 1775 WUblastx.64 (BAB55004) CDNA FLJ14357 fis, BAB5500496% 1020 1502 clone HEMBA1000005, h 91% 27 416 77% 364 417 25% 996 119697% 395 1057 32% 761 862 28% 752 973 28% 1257 1478 45% 611 676 45% 14281499 17% 1002 1229 HLLAX95 588405 1776 WUblastx.64 (Q9GMX5) HYPOTHETICAL12.9 KDA Q9GMX5 52% 541 603 PROTEIN. 65% 381 521 HLMCT51 772579 1780WUblastx.64 (Q9DAD1) 1700013E09RIK Q9DAD1 55% 443 883 PROTEIN. HLMCT95570815 1781 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 53% 1414 1121PRODUCT. HLMDD65 566891 1782 WUblastx.64 (P20591) INTERFERON- MX1_HUMAN100% 489 575 REGULATED RESISTANCE GTP- 70% 580 720 BINDING PROTEIHLMFB62 604915 1785 WUblastx.64 (Q9H700) CDNA: FLJ21617 FIS, Q9H700 68%154 2 CLONE COL07481. HLMFG52 602166 1786 WUblastx.64 (Q9UHT5) PRO1848.Q9UHT5 71% 837 941 HLMFU53 801936 1787 WUblastx.64 (Q9ESD6) LNV. Q9ESD667% 1141 620 HLMHG68 580850 1788 WUblastx.64 (Q9HAI5) CDNA FLJ11583 FIS,Q9HAI5 92% 305 775 CLONE HEMBA1003680, WEAKLY SIMILAR TO PUT HLMHN06853606 1789 WUblastx.64 probable transposase - human pir|S72481|S7248159% 456 286 transposon MER37 80% 262 107 HLMIM84 588487 1791 WUblastx.64(Q9Y3B0) CGI-105 PROTEIN. Q9Y3B0 84% 296 334 98% 645 806 HLMIW76 5708161794 WUblastx.64 (O60448) NEURONAL THREAD O60448 85% 531 490 PROTEINAD7C-NTP. 57% 528 472 59% 600 535 57% 528 472 77% 744 718 63% 601 53666% 752 591 69% 736 590 70% 737 474 HLQAD72 853613 1798 HMMER PFAM:Pancreatic ribonucleases PF00074 213.4 208 564 2.1.1 WUblastx.64ribonuclease 4 (EC 3.1.—.—) precursor - pir|I52489|I52489 90% 124 564human HLQAM30 609880 1799 WUblastx.64 (Q9UHT1) PRO1902 PROTEIN. Q9UHT176% 648 610 57% 490 398 73% 617 480 HLQAM59 560662 1800 WUblastx.64(AAH08373) Similar to hypothetical AAH08373 82% 879 829 protein PRO1722.54% 754 722 63% 1018 881 HLQBB23 745364 1801 WUblastx.64 (Q9CYS6)2810459M11RIK Q9CYS6 44% 38 286 PROTEIN. HLQCY09 745384 1804 WUblastx.64(Q9NX17) CDNA FLJ20489 FIS, Q9NX17 57% 884 843 CLONE KAT08285. 58% 759505 HLQDK45 621414 1807 WUblastx.64 (Q9CPU5) 2700019M19RIK Q9CPU5 100%615 737 PROTEIN. HLQDM47 743237 1808 WUblastx.64 giant protein p619 -human pir|S71752|S71752 92% 377 616 HLTDI20 610269 1817 WUblastx.64(Q9H6C9) CDNA: FLJ22385 FIS, Q9H6C9 70% 5 76 CLONE HRC07610. 95% 58 186HLTDI65 740756 1818 WUblastx.64 (O60448) NEURONAL THREAD O60448 41% 12901382 PROTEIN AD7C-NTP. 50% 1456 1623 46% 1881 2027 47% 1881 2018 54%1958 2029 54% 1878 1949 41% 1513 1605 57% 2095 2157 55% 1955 2038 60%1275 1484 54% 1372 1464 47% 2095 2163 42% 2008 2157 64% 1472 1513 61%1263 1463 36% 1939 2079 32% 1296 1460 50% 1363 1470 61% 2015 2149 46%1315 1608 HLTDK30 834810 1819 WUblastx.64 (Q9HA72) CDNA FLJ12133 FIS,Q9HA72 100% 511 747 CLONE MAMMA1000278 97% 231 506 (SIMILAR TOHYPOTHETIC 97% 740 1180 HLTDL37 638213 1820 WUblastx.64 (Q9Y383) CGI-74PROTEIN. Q9Y383 82% 2 754 66% 1084 1155 37% 974 1078 HLTDU35 827293 1821WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 44% 1118 954 PRODUCT. 62%954 820 HLTEH84 782094 1823 WUblastx.64 (Q9H5P9) CDNA: FLJ23188 FIS,Q9H5P9 97% 15 491 CLONE LNG12038. HLTEL39 853615 1824 WUblastx.64(Q9H743) CDNA: FLJ21394 FIS, Q9H743 39% 1391 1218 CLONE COL03536. 70%1536 1387 HLTEW52 663148 1826 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 70% 1498 1244 CLONE KAIA0536. HLTEZ36 821676 1827 WUblastx.64(Q9H387) PRO2550. Q9H387 76% 7 171 HLTGG14 824068 1828 WUblastx.64(Q9N032) UNNAMED PROTEIN Q9N032 70% 1142 1020 PRODUCT. HLUAF94 7941161829 WUblastx.64 (Q9UI50) PRO0657 (FRAGMENT). Q9UI50 75% 1438 1473 72%1256 1444 HLWAH33 855954 1830 WUblastx.64 (Q9NSI3) PRED43 PROTEIN Q9NSI3100% 1660 1761 (FRAGMENT). 96% 25 102 HLWAO11 885339 1831 WUblastx.64(Q9ES77) POLYDOM PROTEIN Q9ES77 76% 14 2656 PRECURSOR. 32% 14 2371 32% 22383 29% 152 2635 28% 14 2371 27% 14 1699 28% 506 1408 30% 2 628 29% 38640 27% 161 787 28% 1469 2020 31% 2084 2617 34% 2267 2659 33% 14 373 32%80 448 32% 2021 2635 35% 1019 1297 29% 1472 1969 22% 494 1990 33% 17452074 25% 14 478 27% 1067 1597 28% 1886 2179 26% 170 895 24% 1310 177126% 2249 2638 30% 1430 1654 22% 1142 1609 35% 1145 1288 36% 2003 211018% 1382 2194 35% 95 187 24% 455 709 27% 2354 2560 25% 440 673 33% 173271 HLWAX50 809094 1833 WUblastx.64 (AAC08702) Meltrin-L precursor.AAC08702 92% 628 1629 93% 1587 2273 64% 178 255 39% 1553 1669 97% 257661 HLWBK16 638217 1835 WUblastx.64 (Q9UEV9) ACTIN-BINDING Q9UEV9 94%679 1191 PROTEIN HOMOLOG ABP-278. 28% 572 700 52% 590 658 57% 605 65858% 593 658 34% 673 750 29% 682 1185 50% 593 652 37% 593 721 33% 7271164 37% 853 1125 30% 664 1179 53% 590 775 31% 593 775 34% 730 1188 34%691 1185 32% 745 1125 32% 590 775 37% 706 1185 32% 691 1170 32% 688 117937% 688 1173 37% 703 1185 31% 703 1182 28% 703 1176 36% 715 1149 30% 7031188 32% 949 1173 32% 691 1158 28% 691 1185 41% 706 1185 36% 593 775 32%593 775 26% 551 775 31% 691 1179 34% 593 775 30% 748 1125 HLYAJ79 6082891839 WUblastx.64 (Q9B2U5) ATP SYNTHASE 6. Q9B2U5 63% 301 807 HLYAT54581067 1842 WUblastx.64 (Q9H9F0) CDNA FLJ12802 FIS, Q9H9F0 93% 35 220CLONE NT2RP2002124, WEAKLY SIMILAR TO UBI HLYBC81 588490 1843WUblastx.64 (Q9HBW6) NAG13. Q9HBW6 43% 1373 1711 HLYBD09 610019 1844WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 69% 1546 1644 CLONEKAIA0536. 65% 1391 1513 HLYBL67 834538 1845 WUblastx.64 (Q9NRE8) PADI-HPROTEIN. Q9NRE8 64% 335 294 61% 304 158 HLYBN23 667995 1847 WUblastx.64(Q9UI59) PRO0478 PROTEIN. Q9UI59 83% 1397 1450 80% 1333 1395 HLYBT28608152 1850 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 54% 1082 774PRODUCT. HLYBY04 596819 1852 WUblastx.64 (Q9H387) PRO2550. Q9H387 83%1565 1530 71% 1533 1270 HLYCE15 621407 1853 WUblastx.64 (Q9P147)PRO2822. Q9P147 75% 518 420 HLYCH04 608295 1854 WUblastx.64 (O62658)LINE-1 ELEMENT ORF2. O62658 47% 106 273 45% 7 39 HLYDE38 735987 1856WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 47% 987 835 PRODUCT. 68%1091 1005 HLYDG55 835625 1857 WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS,Q9H5R3 73% 638 423 CLONE LNG09295. HLYEA60 685469 1859 WUblastx.64(Q9UI50) PRO0657 (FRAGMENT). Q9UI50 50% 104 181 70% 27 116 HLYEJ14853362 1860 WUblastx.64 (O95498) VASCULAR NON- VNN2_HUMAN 97% 94 1653INFLAMMATORY MOLECULE 2 PRECURSOR (VA HLYEJ44 838149 1861 WUblastx.64(Q9H400) DJ583P15.4.1 (NOVEL Q9H400 100% 124 153 PROTEIN (TRANSLATION OF80% 273 1007 CDNA FLJ20406 (E HLYEU51 607815 1862 WUblastx.64 (Q9NX85)CDNA FLJ20378 FIS, Q9NX85 67% 691 563 CLONE KAIA0536. 78% 857 708HLYGV19 826334 1863 WUblastx.64 (Q9H0W4) HYPOTHETICAL 19.2 KDA Q9H0W472% 195 644 PROTEIN. HMABK52 853363 1864 WUblastx.64 (Q9N032) UNNAMEDPROTEIN Q9N032 62% 1136 1002 PRODUCT. HMACL77 853365 1866 WUblastx.64(O95564) HYPOTHETICAL 30.9 KDA O95564 100% 8 256 PROTEIN. HMACT74 8437441867 WUblastx.64 gamma-interferon-inducible protein pir|A43708|A4370894% 403 639 IP-30 precursor - human HMADJ14 843725 1868 WUblastx.64(Q9H295) DC-SPECIFIC Q9H295 96% 871 945 TRANSMEMBRANE PROTEIN. 90% 47880 HMADJ74 795479 1869 WUblastx.64 (Q9H295) DC-SPECIFIC Q9H295 100%1010 1393 TRANSMEMBRANE PROTEIN. 93% 186 1067 HMAEA58 872563 1870WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 36% 584 519 CLONEKAIA0536. 59% 1339 1172 HMAGF01 837235 1871 WUblastx.64 (Q9UJ41) RAB5GDP/GTP Q9UJ41 89% 71 1543 EXCHANGE FACTOR HOMOLOGUE. HMCED78 8290711873 WUblastx.64 (Q9NWY5) CDNA FLJ20533 FIS, Q9NWY5 98% 380 862 CLONEKAT10931. HMCFN86 886182 1874 WUblastx.64 (Q9BVB2) UNKNOWN (PROTEINQ9BVB2 100% 22 294 FOR IMAGE: 3459631) (FRAGMENT). HMCGJ47 699850 1875WUblastx.64 (AAK29328) Serine AAK29328 91% 11 511 palmitoyltransferase.91% 495 1430 HMCGK88 654854 1876 WUblastx.64 (Q9BT48) SIMILAR TO Q9BT48100% 506 330 HYPOTHETICAL PROTEIN 92% 982 506 FLJ20116. HMCIH27 8620381877 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 70% 1293 1063 CLONECOL04765. HMDAE88 638222 1881 WUblastx.64 (Q9H3C0) PRO0898. Q9H3C0 57%1001 843 81% 844 734 HMDAM39 602907 1885 WUblastx.64 (Q9P195) PRO1722.Q9P195 66% 648 388 HMEAA41 587304 1886 WUblastx.64 (Q9H6H3) CDNA:FLJ22282 FIS, Q9H6H3 100% 9 419 CLONE HRC03861. HMEEH21 603187 1888WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 65% 280 504 PRODUCT. HMEEZ07638225 1890 WUblastx.64 (Q9UK97) F-BOX ONLY PROTEIN FBX9_HUMAN 100% 795917 9. HMEIH57 840370 1892 WUblastx.64 (Q14288) HYPOTHETICAL Q14288 74%238 11 PROTEIN (FRAGMENT). 58% 1348 1190 50% 1236 256 HMEIJ21 7672761893 WUblastx.64 (Q9H067) HYPOTHETICAL 66.5 KDA Q9H067 61% 2388 1777PROTEIN. 50% 828 709 56% 1676 840 HMEJC96 761218 1895 WUblastx.64(O60836) MEMBRANE O60836 86% 193 669 GLYCOPROTEIN GP36 PRECURSOR.HMEJK28 825591 1897 WUblastx.64 (O00479) NON-HISTONE O00479 54% 273 485CHROMOSOMAL PROTEIN (HIGH- MOBILITY GROUP (NONHIS HMEKW44 825499 1899WUblastx.64 (O18975) HYPOTHETICAL 16.6 KDA O18975 71% 7 198 PROTEIN(FRAGMENT). HMEKW71 855955 1900 WUblastx.64 (Q9UHF1) NOTCH4-LIKE PROTEINQ9UHF1 96% 579 758 (HYPOTHETICAL 29.6 KDA PROTEIN). HMHBI09 847402 1903WUblastx.64 (AAH07644) Similar to RIKEN cDNA AAH07644 93% 39 6839430029K10 gene (F HMHBI93 844729 1904 WUblastx.64 (Q9Z1S4)TGFB1-INDUCED ANTI- TIAF_MOUSE 90% 1391 1735 APOPTOTIC FACTOR 1 (12 KDATGF- HMIAC52 825484 1906 WUblastx.64 (AAH00713) Neighbor of A-kinaseAAH00713 30% 941 1201 anchoring protein 9 52% 988 1056 75% 112 927HMIAG42 846339 1908 WUblastx.64 (AAK54122) RGS20 ret splice variantAAK54122 78% 1071 1730 1. HMIAG55 736020 1909 WUblastx.64 (AAD20460)Ribosomal protein L11. AAD20460 67% 424 609 HMIAG72 824091 1910WUblastx.64 (O60519) CRE BINDING PROTEIN- O60519 85% 318 677 LIKE 2.HMIAO82 833070 1912 WUblastx.64 hypothetical protein pir|T46340|T4634058% 32 358 DKFZp434B0814.1 - human 50% 443 742 (fragment) HMIAR42 8090961913 WUblastx.64 (Q9BVE4) SIMILAR TO Q9BVE4 87% 1046 1165INTERFERON-RELATED 91% 831 1052 DEVELOPMENTAL REGULATOR 99% 7 849 1.HMIAV33 668252 1914 WUblastx.64 (Q9UN80) HYPOTHETICAL 149.0 KDA Q9UN8034% 1051 1182 PROTEIN. 48% 1167 1337 40% 603 430 41% 138 10 28% 1015 61138% 431 162 HMIBE95 804597 1917 WUblastx.64 probable transposase - humanpir|S72481|S72481 60% 1932 2075 transposon MER37 64% 1221 1355 42% 13551948 HMKAN71 884161 1920 WUblastx.64 (Q96G03) Unknown (protein forQ96G03 100% 12 1385 MGC: 19508). HMKBA33 596949 1921 WUblastx.64(Q9N083) UNNAMED PORTEIN Q9N083 47% 1147 1010 PRODUCT. 44% 1248 1162 75%1441 1382 57% 1314 1147 33% 383 261 65% 1691 1482 HMKCK32 561576 1923WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 53% 619 335 PRODUCT. HMKDG69588407 1927 WUblastx.64 pro-pol-dUTPase polyprotein - murinepir|T29097|T29097 59% 104 24 endogenous retrovirus ERV-L 34% 700 116(fragment) HMKDM80 608168 1928 WUblastx.64 (Q9H6G8) CDNA: FLJ22294 FIS,Q9H6G8 74% 178 11 CLONE HRC04426. HMKEG88 634245 1929 WUblastx.64(O00378) PUTATIVE P150. O00378 47% 294 4 HMMAA09 822859 1930 WUblastx.64(AAK55521) PRO0764. AAK55521 68% 1305 1249 67% 1271 1014 HMMAK92 6101001931 WUblastx.64 (Q9CZ33) 2810408E11RIK Q9CZ33 86% 15 152 PROTEIN.HMMBF22 780406 1934 WUblastx.64 (Q9H6V7) CDNA: FLJ21825 FIS, Q9H6V7 56%1228 1341 CLONE HEP01348. 93% 407 499 58% 824 1159 HMMBH94 607463 1936WUblastx.64 (AAK55521) PRO0764. AAK55521 80% 857 813 71% 835 593 HMMBK55608179 1937 WUblastx.64 (Q9H397) PRO2852. Q9H397 72% 521 468 36% 480 36170% 691 527 HMMBT47 804594 1941 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 66% 1238 1203 CLONE KAIA0536. 54% 1206 874 HMMCD35 607840 1942WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 59% 813 676 CLONECOL04765. 58% 661 512 HMMCD95 603202 1943 WUblastx.64 (Q9N083) UNNAMEDPORTEIN Q9N083 58% 1498 1397 PRODUCT. 63% 1643 1494 HMPAB26 580854 1944WUblastx.64 (P78560) DEATH DOMAIN CRAD_HUMAN 100% 66 365 CONTAININGPROTEIN CRADD (CASPASE AND HMQAI38 589964 1946 WUblastx.64immune-responsive gene 1 - mouse pir|I54546|I54546 71% 11 1363(fragment) HMQAT69 799551 1947 WUblastx.64 (Q9Y5X1) SORTING NEXIN 9 (SH3SNX9_HUMAN 94% 739 1842 AND PX DOMAIN-CONTAINING 82% 660 809 PROT 93% 56748 HMQBL90 600363 1948 WUblastx.64 pre-B cell Ig lambda-like omegalight pir|A33911|A33911 52% 879 1091 chain (non-rearranging) 14.1 -human 76% 974 1309 HMQBV82 826522 1949 WUblastx.64 (Q9BGW3) HYPOTHETICAL13.5 KDA Q9BGW3 61% 739 876 PROTEIN. 72% 969 868 40% 651 592 HMQCA75767086 1950 WUblastx.64 (AAK55521) PRO0764. AAK55521 62% 1235 1071 72%1072 944 HMQCB37 732168 1951 WUblastx.64 (AAK55521) PRO0764. AAK5552185% 426 446 71% 1087 1149 50% 872 1042 79% 503 904 HMQCX41 603388 1953WUblastx.64 (O60448) NEURONAL THREAD O60448 43% 192 260 PROTEINAD7C-NTP. 55% 16 204 HMQDM09 664494 1954 WUblastx.64 (Q9NZV6)SELENOPROTEIN X 1 SELX_HUMAN 98% 38 385 (PROTEIN HSPC270). HMSAP33731969 1956 WUblastx.64 (Q9P147) PRO2822. Q9P147 83% 1526 1398 HMSAZ48877650 1957 WUblastx.64 probable pol polyprotein-relatedpir|S21348|S21348 46% 793 1218 protein 4 - rat 66% 722 784 HMSBN18847405 1958 WUblastx.64 (O95789) ZNF258. O95789 65% 165 329 HMSBS25826487 1959 WUblastx.64 (Q9Y642) K: CL COTRANSPORTER Q9Y642 77% 10191189 3. 81% 337 384 100% 257 346 HMSBU14 844443 1960 WUblastx.64hypothetical protein pir|T47135|T47135 41% 954 1184 DKFZp761L0812.1 -human 63% 1192 1488 (fragment) HMSCB94 847406 1962 WUblastx.64 (Q9NX17)CDNA FLJ20489 FIS, Q9NX17 45% 1690 1589 CLONE KAT08285. 80% 1931 1683HMSCK12 825475 1963 WUblastx.64 (Q9P195) PRO1722. Q9P195 62% 771 613 81%622 491 HMSCV75 838530 1965 WUblastx.64 (Q9NRE8) PADI-H PROTEIN. Q9NRE840% 1565 1461 67% 1438 1301 HMSCW44 716249 1967 WUblastx.64 (Q9P195)PRO1722. Q9P195 47% 1251 1102 66% 1112 942 HMSCZ19 847408 1968WUblastx.64 (O60427) BC269730_2 O60427 84% 621 1124 (HYPOTHETICAL 52.0KDA 94% 1 675 PROTEIN) (FATTY ACID DESAT HMSDI67 827298 1969 WUblastx.64probable pol polyprotein-related pir|S21348|S21348 55% 1255 1121 protein4-rat 38% 1748 1284 HMSDR28 801948 1971 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 76% 1097 1035 CLONE COL04765. 72% 1317 1102 HMSFT25581069 1972 WUblastx.64 (AAK55521) PRO0764. AAK55521 43% 1088 1198 61%918 1025 HMSFW52 603177 1973 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 67% 1380 1631 CLONE KAIA0536. HMSGU30 847409 1975 WUblastx.64(Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 55% 1718 1494 PROTEIN. HMSHB42792385 1976 WUblastx.64 (Q9NR81) RHOGEF Q9NR81 97% 4 867 (HYPOTHETICAL59.8 KDA PROTEIN). HMSHB42 600401 1977 WUblastx.64 (Q9NR81) RHOGEFQ9NR81 99% 4 1203 (HYPOTHETICAL 59.8 KDA PROTEIN). HMSHN72 855917 1978WUblastx.64 (Q98SS5) DOUBLECORTIN. Q98SS5 91% 650 754 HMSHW73 7040991980 WUblastx.64 (Q9P195) PRO1722. Q9P195 62% 2214 2134 65% 2131 206371% 2072 1935 HMSII36 825453 1982 WUblastx.64 (AAK55521) PRO0764.AAK55521 61% 23 61 72% 51 161 HMSIT42 581070 1983 WUblastx.64 (Q9P147)PRO2822. Q9P147 80% 1160 936 HMSJB08 877651 1984 WUblastx.64 (Q9D2Y4)9130019I15RIK Q9D2Y4 56% 1037 612 PROTEIN. 58% 1987 1028 HMSJR44 6380981987 WUblastx.64 (Q9P195) PRO1722. Q9P195 73% 798 721 43% 1168 1037 82%853 803 36% 1633 1511 64% 995 843 HMSKQ91 825450 1988 WUblastx.64(Q9HBN2) HYPOTHETICAL 15.8 KDA Q9HBN2 68% 864 742 PROTEIN. HMTAF92740784 1990 WUblastx.64 (Q9Y6I4) UBIQUITIN CARBOXYL- UBP3_HUMAN 93% 22112167 TERMINAL HYDROLASE 3 (EC 84% 2053 644 3.1.2. HMTAT36 811885 1991WUblastx.64 (Q9H6Z9) CDNA: FLJ21620 FIS, Q9H6Z9 100% 1 117 CLONECOL07838. HMUAD65 809097 1993 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS,Q9H743 67% 1524 1213 CLONE COL03536. HMUBK53 553624 1997 WUblastx.64(Q9H8X7) CDNA FLJ13156 FIS, Q9H8X7 86% 18 398 CLONE NT2RP3003490, WEAKLYSIMILAR TO HOM HMUBY57 844800 2001 WUblastx.64 (Q9H5R3) CDNA: FLJ23147FIS, Q9H5R3 78% 1827 1609 CLONE LNG09295. HMUBZ15 609837 2002WUblastx.64 (Q9BU61) SIMILAR TO NUCLEAR Q9BU61 60% 968 1012 PROTEIN E3-3ORF1. 100% 412 963 HMVAL15 822860 2003 WUblastx.64 A-kinase anchorprotein 95 - human pir|T13161|T13161 83% 1 348 HMVBC84 743191 2004WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 47% 1019 957 CLONECOL04765. 76% 1135 1019 HMVBD68 831130 2005 WUblastx.64 catalase (EC1.11.1.6) - pir|I40767|I40767 85% 207 103 Campylobacter jejuni HMVCG17846161 2006 WUblastx.64 (Q9NZS9) APOPTOSIS Q9NZS9 96% 282 458 REGULATOR.33% 89 151 100% 204 290 HMVDT89 831127 2011 WUblastx.64 (Q9HAT2) SIALICACID-SPECIFIC Q9HAT2 90% 2 385 ACETYLESTERASE II. 98% 384 809 HMVDT89875313 2012 WUblastx.64 (Q9HAT2) SIALIC ACID-SPECIFIC Q9HAT2 90% 2 385ACETYLESTERASE II. 98% 384 809 HMWAO65 839268 2013 WUblastx.64 (Q9P0A1)HSPC280 (FRAGMENT). Q9P0A1 100% 30 371 HMWAO82 825427 2014 WUblastx.64(Q9NX17) CDNA FLJ20489 FIS, Q9NX17 84% 461 366 CLONE KAT08285. HMWBK35566888 2016 WUblastx.64 (Q9NX17) CDNA FLJ20489 FIS, Q9NX17 76% 956 918CLONE KAT08285. 64% 919 650 HMWBL38 602940 2018 WUblastx.64 (Q9NX17)CDNA FLJ20489 FIS, Q9NX17 76% 743 615 CLONE KAT08285. 65% 916 719HMWBM48 566828 2019 WUblastx.64 ribosomal protein L3 precursor,pir|A27294|R5HUL3 80% 609 379 mitochondrial - human 100% 794 609 HMWCG28847413 2020 WUblastx.64 (Q9P1S9) KINASE DEFICIENT Q9P1S9 84% 35 892PROTEIN KDP (FRAGMENT). HMWCP85 757974 2021 WUblastx.64 Na+-dependentvitamin C (L-ascorbic pir|JC7182|JC7182 64% 37 297 acid) transporterSVCT1 - human 79% 1181 1507 61% 698 1264 86% 369 737 HMWDG30 623758 2022WUblastx.64 (Q9VQ76) CG4263 PROTEIN. Q9VQ76 43% 1364 1411 37% 30 668HMWDU20 695743 2023 WUblastx.64 (Q9NXB8) CDNA FLJ20335 FIS, Q9NXB8 89%918 1034 CLONE HEP11429 (FRAGMENT). 75% 347 454 93% 1004 1819 HMWDZ63608146 2025 WUblastx.64 (P41565) ISOCITRATE IDHG_RAT 33% 399 301DEHYDROGENASE [NAD] 100% 169 74 SUBUNIT GAMMA, MITO HMWEA77 839221 2026WUblastx.64 (Q9BGX7) HYPOTHETICAL 13.0 KDA Q9BGX7 60% 1066 1110 PROTEIN.70% 1100 1282 HMWEC03 598902 2027 WUblastx.64 (Q9P0X2) HEAT SHOCKPROTEIN Q9P0X2 100% 1066 1365 HSP60. 91% 573 1064 99% 105 572 HMWEF46825433 2028 WUblastx.64 (Q9H0G8) HYPOTHETICAL 14.0 KDA Q9H0G8 100% 11131226 PROTEIN. HMWEK43 847414 2029 WUblastx.64 (Q9H8K0) CDNA FLJ13520FIS, Q9H8K0 46% 940 1167 CLONE PLACE1005828. HMWEM23 863105 2030WUblastx.64 (Q96QF0) SSX2 interacting protein Q96QF0 96% 1086 1532hRabin3A, isoform alpha2. 96% 128 1114 HMWEM23 859387 2031 WUblastx.64(Q9H673) CDNA: FLJ22548 FIS, Q9H673 95% 1086 1532 CLONE HSI00519. 96%152 1114 HMWEU96 1310888 2033 WUblastx.64 (Q9UH62) HYPOTHETICAL 42.5 KDAQ9UH62 88% 91 1227 PROTEIN (ALEX3) (ALEX3 PROTEIN). HMWEU96 601698 3110WUblastx.64 (AB039669) ALEX3 [Homo sapiens] dbj|BAA94602.1| 88% 86 1222HMWEX02 596821 2034 WUblastx.64 (Q9H7H4) FLJ00116 PROTEIN Q9H7H4 67% 5091000 (FRAGMENT). HMWFB65 638102 2035 WUblastx.64 (O95427) MCD4P HOMOLOG.O95427 74% 37 591 95% 894 959 100% 611 898 68% 9 59 HMWFD77 610105 2036WUblastx.64 (Q9P1N7) PRO0974. Q9P1N7 83% 459 494 55% 293 433 HMWFO25566855 2037 WUblastx.64 (Q9HA89) CDNA FLJ12060 FIS, Q9HA89 100% 742 816CLONE HEMBB1002142. HMWGM41 847415 2039 WUblastx.64 (Q9H8P0) CDNAFLJ13352 FIS, Q9H8P0 84% 33 986 CLONE OVARC1002165, WEAKLY SIMILAR TO3-O HMWGO95 582078 2040 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H72882% 1446 1396 CLONE COL04765. 68% 1390 1145 HMWGV85 847416 2041WUblastx.64 (Q9H8H3) CDNA FLJ13631 FIS, Q9H8H3 100% 41 298 CLONEPLACE1011090, HIGHLY SIMILAR TO HOM HMWGZ42 824259 2042 WUblastx.64(Q9BVD9) UNKNOWN (PROTEIN Q9BVD9 50% 262 309 FOR MGC: 5149). 42% 13161534 HMWIQ26 722234 2045 WUblastx.64 (Q9NGC3) CENTAURIN GAMMA Q9NGC3 48%844 395 1A PROTEIN. 47% 298 5 43% 221 162 21% 388 218 HMWIU49 8008942046 WUblastx.64 (O95831) PROGRAMED CELL PCD8_HUMAN 98% 3 407 DEATHPROTEIN 8, 38% 1384 1500 MITOCHONDRIAL PREC 94% 379 1362 HMWJJ62 8386122047 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 71% 657 875PROTEIN. HMWJJ64 581071 2048 WUblastx.64 (Q9D0Q7) 2600005P05RIK Q9D0Q778% 12 878 PROTEIN. HNAAD76 596801 2049 WUblastx.64 (Q9N083) UNNAMEDPORTEIN Q9N083 65% 1650 1528 PRODUCT. 59% 1807 1646 HNALD94 844722 2051WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 70% 764 817 CLONEKAIA0536. 72% 816 926 HNALE44 785045 2052 WUblastx.64 (Q9Y503) FILAMIN,MUSCLE Q9Y503 100% 12 86 ISOFORM. 30% 916 1170 72% 12 86 62% 12 83 52%12 62 31% 783 896 60% 18 86 51% 12 95 45% 12 77 36% 18 92 36% 9 95 95%79 1170 31% 916 1170 28% 49 795 36% 1096 1170 33% 1127 1207 35% 901 117031% 112 801 30% 1823 1927 29% 925 1170 39% 916 1170 30% 916 1170 27% 217504 29% 18 98 46% 15 86 29% 910 1170 30% 901 1170 34% 79 792 42% 79 79825% 940 1170 30% 79 792 32% 916 1170 38% 340 864 29% 88 855 30% 88 79232% 109 795 33% 16 798 26% 103 855 29% 916 1170 25% 925 1170 33% 85 79230% 262 795 29% 109 816 34% 916 1164 32% 520 792 26% 751 1170 29% 430792 33% 940 1170 36% 12 77 31% 82 792 34% 79 783 HNEAK38 631279 2056WUblastx.64 (Q26195) PVA1 GENE. Q26195 71% 1204 1100 47% 1383 1333 59%1358 1197 HNEAK65 604991 2057 WUblastx.64 (Q9P195) PRO1722. Q9P195 72%570 427 82% 715 560 HNEBY79 841769 2059 WUblastx.64 (Q9UI50) PRO0657(FRAGMENT). Q9UI50 58% 944 1153 72% 1270 1488 HNECL75 782493 2061WUblastx.64 (Q9HCX0) PELLINO. Q9HCX0 96% 215 649 100% 627 1268 HNECX90834776 2062 WUblastx.64 (Q9UJL8) HYPOTHETICAL 43.5 KDA Q9UJL8 84% 811265 PROTEIN. HNECX90 881133 2063 WUblastx.64 (Q9UJL8) HYPOTHETICAL 43.5KDA Q9UJL8 84% 81 1265 PROTEIN. HNEDP75 581072 2065 WUblastx.64 (Q9NX85)CDNA FLJ20378 FIS, Q9NX85 63% 910 722 CLONE KAIA0536. HNEDQ02 8460612066 WUblastx.64 (Q9HA25) CDNA FLJ12374 FIS, Q9HA25 76% 941 1063 CLONEMAMMA1002470, 93% 1018 2013 WEAKLY SIMILAR TO PRO HNEDU46 695745 2067WUblastx.64 (Q9H3P1) 6-PHOSPHOFRUCTO-2- Q9H3P1 100% 343 420 KINASE HEARTISOFORM. 95% 137 208 95% 766 825 HNFAD50 839369 2068 WUblastx.64(Q9H175) HYPOTHETICAL 59.6 KDA Q9H175 47% 128 859 PROTEIN. HNFAD50843242 2069 WUblastx.64 (Q9H175) HYPOTHETICAL 59.6 KDA Q9H175 54% 50 379PROTEIN. HNFAG67 804546 2070 WUblastx.64 (O60759) CYTOHESIN BINDINGO60759 73% 327 857 PROTEIN HE. HNFCJ77 886185 2071 WUblastx.64 (Q9BVD9)UNKNOWN (PROTEIN Q9BVD9 74% 2342 2250 FOR MGC: 5149). 63% 1819 1763 73%1763 1719 61% 2034 1792 HNFCY57 877653 2073 WUblastx.64 (AAL12497)Cryopyrin. AAL12497 91% 8 2203 HNFDL89 823362 2074 WUblastx.64 (Q9BT07)UNKNOWN (PROTEIN Q9BT07 46% 2098 2193 FOR MGC: 4033). 100% 1964 2101HNFDU92 602933 2076 WUblastx.64 (O60448) NEURONAL THREAD O60448 60% 703407 PROTEIN AD7C-NTP. 48% 721 425 88% 435 409 74% 570 388 56% 764 62756% 522 388 43% 571 503 43% 495 388 57% 745 683 48% 757 677 HNFDY09843300 2077 WUblastx.64 (Q9BZ41) BA476I15.3 (NOVEL Q9BZ41 92% 1243 1281PROTEIN SIMILAR TO SEPTIN) 75% 1280 1363 (FRAGMENT). 53% 1104 1238HNFDY31 724955 2078 WUblastx.64 (O00571) DEAD-BOX PROTEIN 3 DDX3_HUMAN64% 169 621 (HELICASE-LIKE PROTEIN 2) 98% 693 1028 (HLP2 HNFEA17 7532422079 WUblastx.64 (Q9BRG9) UNKNOWN (PROTEIN Q9BRG9 94% 965 1318 FOR MGC:11314). HNFEP55 722236 2080 WUblastx.64 (Q9NW80) HYPOTHETICAL 73.6 KDAQ9NW80 41% 877 966 PROTEIN. 65% 158 862 HNFET12 824170 2081 WUblastx.64(Q9H743) CDNA: FLJ21394 FIS, Q9H743 75% 1217 1182 CLONE COL03536. 75%1182 952 HNFFR59 634649 2082 WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS,Q9HA67 65% 1613 1485 CLONE MAMMA1000472. HNFGR15 844044 2084 WUblastx.64(Q99770) HYPOTHETICAL 15.4 KDA Q99770 53% 1128 1172 PROTEIN. 90% 824 886HNFGW53 589525 2086 WUblastx.64 (Q9NUM6) CDNA FLJ11267 FIS, Q9NUM6 53%777 938 CLONE PLACE1009174. HNFHV68 567445 2089 WUblastx.64pro-pol-dUTPase polyprotein - murine pir|T29097|T29097 44% 380 24endogenous retrovirus ERV-L (fragment) HNFIE15 898153 2090 WUblastx.64(Q9H387) PRO2550. Q9H387 72% 2374 2300 62% 2576 2370 HNFIE29 852233 2091WUblastx.64 (Q9HBS7) HYPOTHETICAL 14.2 KDA Q9HBS7 42% 1484 1407 PROTEIN.54% 1419 1168 HNFJE27 825400 2093 WUblastx.64 (Q9NUQ9) CDNA FLJ11197FIS, Q9NUQ9 93% 986 1123 CLONE PLACE1007690 (HYPOTHETICAL 36.7 KDAHNGAC71 695746 2095 WUblastx.64 (Q9GKW4) HYPOTHETICAL 12.6 KDA Q9GKW477% 64 11 PROTEIN. 85% 138 79 HNGAX06 841890 2099 WUblastx.64 (Q14288)HYPOTHETICAL Q14288 100% 22 108 PROTEIN (FRAGMENT). HNGBE44 825391 2103WUblastx.64 (O00437) AXONEMAL DYNEIN O00437 71% 323 502 HEAVY CHAIN(FRAGMENT). HNGBI83 566815 2105 WUblastx.64 (O60448) NEURONAL THREADO60448 69% 322 420 PROTEIN AD7C-NTP. 53% 122 160 73% 331 420 74% 13 8759% 10 87 51% 12 104 55% 22 102 61% 42 80 55% 28 81 HNGCF29 580201 2111WUblastx.64 (Q9H387) PRO2550. Q9H387 71% 1112 1074 60% 1069 842 HNGCF64823147 2112 WUblastx.64 (AAH07558) Unknown (protein for AAH07558 48%1893 1765 MGC: 15483). 55% 1763 1629 HNGDF54 702002 2113 WUblastx.64(Q9N8T2) POSSIBLE SRPA. Q9N8T2 29% 13 654 27% 14 679 27% 14 679 29% 13654 HNGDH27 581074 2115 WUblastx.64 (Q92722) RETINOBLASTOMA 1. Q9272245% 290 99 HNGDN07 847081 2116 WUblastx.64 (Q9UI50) PRO0657 (FRAGMENT).Q9UI50 80% 1091 966 HNGEE06 689506 2122 WUblastx.64 (Q9H960) CDNAFLJ12988 FIS, Q9H960 43% 66 1 CLONE NT2RP3000080. 60% 1040 909 HNGEN32621308 2128 WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, Q9H5R3 76% 361 399CLONE LNG09295. 80% 408 557 HNGET33 825378 2131 WUblastx.64 (Q9H387)PRO2550. Q9H387 78% 459 755 HNGEZ02 825376 2134 WUblastx.64 (Q9NX85)CDNA FLJ20378 FIS, Q9NX85 81% 840 938 CLONE KAIA0536. HNGEZ90 6348582135 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 72% 1119 1045 CLONECOL04765. 71% 956 810 HNGFD30 612782 2138 WUblastx.64 (O75423) O7542372% 264 100 ORF3, SPLICEVARIANT_A. HNGFD31 663532 2139 WUblastx.64(Q9HA67) CDNA FLJ12155 FIS, Q9HA67 76% 574 624 CLONE MAMMA1000472. 78%491 574 HNGFG04 772548 2141 WUblastx.64 (Q9Y485) X-LIKE 1 PROTEIN.Q9Y485 100% 423 533 HNGFI21 581075 2145 WUblastx.64 (Q9EQC8) PAPILLARYRENAL Q9EQC8 58% 117 296 CELL CARCINOMA-ASSOCIATED PROTEIN. HNGFT70581079 2150 WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, Q9H5R3 76% 1073 855CLONE LNG09295. HNGGF13 638117 2153 WUblastx.64 hypothetical proteinhc1 - mouse pir|S26689|S26689 38% 13 183 (fragment) 37% 13 186 HNGGK63822862 2154 WUblastx.64 (Q9QZ22) OLFACTORY Q9QZ22 59% 1224 1003RECEPTOR. 88% 985 278 HNGGT10 866179 2159 HMMER PFAM: 3-betahydroxysteroid PF01073 263.9 19 468 2.1.1 dehydrogenase/isomerase familyWUblastx.64 (Q9BSN9) 3 BETA-HYDROXY- Q9BSN9 75% 10 480 DELTA5-C27-STEROID OXIDOREDUCTASE. HNGHB89 722238 2161 WUblastx.64 (O88748)E-STOP PROTEIN. O88748 100% 153 37 HNGHD07 608149 2162 WUblastx.64(Q9BRA2) UNKNOWN (PROTEIN Q9BRA2 51% 588 755 FOR MGC: 14353). 70% 746943 HNGIK07 825360 2168 WUblastx.64 (Q9H3I6) BRAIN MY040 PROTEIN. Q9H3I676% 1139 912 HNGIM40 747699 2169 WUblastx.64 (Q9H5W7) CDNA: FLJ22921FIS, Q9H5W7 87% 2354 2208 CLONE KAT06711. HNGIM83 751714 2170 HMMERPFAM: HCO3-transporter family PF00955 117.9 72 290 2.1.1 WUblastx.64(Q9UIB9) BICARBONATE Q9UIB9 74% 9 290 TRANSPORTER. HNGIO93 897527 2171HMMER PFAM: Ribosomal L27 protein PF01016 71.7 −21 −233 2.1.1WUblastx.64 (Q9P0M9) HSPC250 Q9P0M9 88% 151 594 (MITOCHONDRIAL RIBOSOMALPROTEIN L27) (L27MT) (HYPOT HNGIU16 826717 2173 WUblastx.64 (Q9H387)PRO2550. Q9H387 78% 2322 2215 76% 2505 2467 78% 2467 2315 HNGIX91 5645742174 WUblastx.64 (AAH07609) Similar to hypothetical AAH07609 100% 956982 protein PRO1722. 77% 885 950 76% 739 891 HNGJU60 825336 2182WUblastx.64 (Q9GW02) EXTREMELY Q9GW02 51% 166 258 CYSTEINE/VALINE RICH50% 166 261 PROTEIN (FRAGMENT). 46% 166 261 56% 169 258 48% 169 261 45%169 261 48% 169 261 40% 290 487 44% 287 487 41% 290 487 41% 169 261 44%287 490 46% 169 258 55% 231 257 44% 290 487 45% 287 487 42% 287 487 44%290 487 44% 290 490 48% 163 261 46% 166 261 48% 169 261 48% 163 261 44%287 487 40% 172 261 45% 169 261 43% 287 487 48% 169 261 HNGKW35 8994082184 WUblastx.64 (O00627) HYPOTHETICAL 11.0 KDA O00627 53% 292 477PROTEIN (ORF2). HNGKY94 835021 2185 WUblastx.64 (Q9H728) CDNA: FLJ21463FIS, Q9H728 66% 581 501 CLONE COL04765. 69% 777 583 HNHAB38 609892 2188WUblastx.64 (Q9H387) PRO2550. Q9H387 68% 635 339 HNHAD34 612845 2190WUblastx.64 (Q9N032) UNNAMED PROTEIN Q9N032 64% 1056 922 PRODUCT.HNHAY26 704789 2198 WUblastx.64 (Q9H397) PRO2852. Q9H397 85% 2098 1919HNHAZ20 839696 2200 WUblastx.64 (Q9C074) HYPOTHETICAL 73.9 KDA Q9C07481% 1213 11 PROTEIN (FRAGMENT). HNHBE38 562730 2202 WUblastx.64(AAK55521) PRO0764. AAK55521 65% 1131 1072 72% 1097 855 HNHBG18 6049242203 WUblastx.64 (O00365) L1 ELEMENT L1.15 P40 O00365 29% 717 271PROTEIN. HNHBM16 566866 2205 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS,Q9H743 87% 80 33 CLONE COL03536. 71% 310 80 HNHCH78 694657 2206WUblastx.64 (AAH07609) Similar to hypothetical AAH07609 100% 270 290protein PRO1722. 88% 194 271 75% 49 195 HNHCT47 634691 2210 WUblastx.64(Q9H728) CDNA: FLJ21463 FIS, Q9H728 46% 434 396 CLONE COL04765. 56% 621448 HNHDC52 812424 2213 WUblastx.64 (O00365) L1 ELEMENT L1.15 P40 O0036532% 1038 910 PROTEIN. 68% 904 269 HNHDI17 738043 2216 WUblastx.64(O95662) POT. ORF VI O95662 80% 265 327 (FRAGMENT). 56% 5 295 HNHDR57638121 2219 WUblastx.64 (O60448) NEURONAL THREAD O60448 58% 1193 1095PROTEIN AD7C-NTP. 63% 496 440 56% 485 393 50% 503 426 64% 1195 1124 33%658 440 41% 1186 1043 40% 402 322 61% 1065 874 51% 1177 923 36% 486 33131% 1090 455 53% 437 393 60% 1168 863 HNHDW34 607867 2222 WUblastx.64(Q9H728) CDNA: FLJ21463 FIS, Q9H728 62% 1175 1017 CLONE COL04765. 56%961 671 HNHEF70 610115 2228 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS,Q9H728 80% 481 437 CLONE COL04765. 77% 417 352 50% 650 462 HNHEL22607421 2231 WUblastx.64 (Q9NUL2) CDNA FLJ11292 FIS, Q9NUL2 71% 280 342CLONE PLACE1009665. 72% 363 656 HNHEN70 854712 2232 WUblastx.64olfactory receptor OR18 - rat pir|S29710|S29710 67% 34 567 HNHEP41638124 2234 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 41% 915 730CLONE KAIA0536. 73% 736 635 HNHEZ76 618544 2238 WUblastx.64 (Q9HA67)CDNA FLJ12155 FIS, Q9HA67 72% 359 466 CLONE MAMMA1000472. HNHFF81 7320752240 WUblastx.64 (Q9GMP5) HYPOTHETICAL 6.6 KDA Q9GMP5 71% 1208 1333PROTEIN. HNHFR42 638127 2242 WUblastx.64 (Q9UI50) PRO0657 (FRAGMENT).Q9UI50 75% 522 427 HNHGD95 609905 2244 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 46% 430 392 CLONE COL04765. 56% 608 444 HNHGR82617117 2245 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 48% 125 39PROTEIN. 56% 262 110 HNHGY77 638128 2247 WUblastx.64 (Q9BZV1) UBXDOMAIN- Q9BZV1 53% 292 248 CONTAINING PROTEIN 1. 100% 212 90 HNHHA47658743 2248 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 65% 983 864CLONE KAIA0536. 66% 1138 1001 HNHKI74 777856 2252 WUblastx.64 (Q9BGX7)HYPOTHETICAL 13.0 KDA Q9BGX7 64% 350 541 PROTEIN. HNHLD80 839255 2254WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, Q9HA67 44% 563 414 CLONEMAMMA1000472. 72% 700 572 HNHLS76 853372 2255 WUblastx.64 (O15410)CAGH45. O15410 74% 146 316 HNHMY76 838256 2259 WUblastx.64 (Q9NX85) CDNAFLJ20378 FIS, Q9NX85 75% 576 647 CLONE KAIA0536. 83% 520 555 75% 659 778HNKAA76 802009 2264 WUblastx.64 (Q9BTI4) SIMILAR TO RIKEN Q9BTI4 84% 3231492 CDNA 8430408O15 GENE. 60% 353 421 HNTAF42 824082 2265 WUblastx.64(Q9NX17) CDNA FLJ20489 FIS, Q9NX17 63% 380 673 CLONE KAT08285. HNTCG32897776 2266 HMMER PFAM: Sodium/hydrogen exchanger PF00999 244.7 178 7892.1.1 family WUblastx.64 (AAK54508) Nonselective sodium AAK54508 60% 13837 potassium/proton exc 52% 772 1089 HNTNY89 886188 2267 WUblastx.64(Q9H400) DJ583P15.4.1 (NOVEL Q9H400 90% 338 1006 PROTEIN (TRANSLATION OF100% 158 187 CDNA FLJ20406 (E 68% 307 354 HNTRQ40 809100 2269WUblastx.64 (Q9UBC2) EPIDERMAL GROWTH Q9UBC2 64% 1498 1857 FACTORRECEPTOR SUBSTRATE 76% 11 451 EPS15R. 92% 492 1604 66% 1810 1845 57%1567 1608 36% 32 178 40% 202 486 40% 1540 1623 48% 1567 1686 41% 13981544 33% 1395 1589 50% 1452 1544 34% 1377 1547 36% 495 695 35% 20 19640% 519 623 23% 750 1610 HOAAJ09 654862 2273 WUblastx.64 (Q9BVD9)UNKNOWN (PROTEIN Q9BVD9 82% 560 510 FOR MGC: 5149). 77% 769 572 HOAAL10566867 2274 WUblastx.64 (Q9P1N7) PRO0974. Q9P1N7 42% 1113 1217 58% 9291129 HOABC12 801922 2276 WUblastx.64 (Q13391) HYPOTHETICAL Q13391 100%208 405 PROTEIN 384D8_6. 97% 5 208 HOABH36 740758 2277 WUblastx.64(Q9BSY5) UNKNOWN (PROTEIN Q9BSY5 94% 147 1073 FOR IMAGE: 3831362) 86%1078 1353 (FRAGMENT). 83% 10 177 HOBNA89 604999 2278 WUblastx.64microtubule-associated pir|A54602|A54602 51% 369 7 serine/threonineprotein kinase MAST205 - mouse HOBNF51 580861 2279 WUblastx.64 (O00410)IMPORTIN BETA-3 IMB3_HUMAN 95% 10 414 SUBUNIT (KARYOPHERIN BETA-3 20%271 375 SUBUNI 99% 395 1051 HODAH24 656887 2280 WUblastx.64 (Q9BVD9)UNKNOWN (PROTEIN Q9BVD9 68% 1326 1189 FOR MGC: 5149). HODAH46 8625512281 WUblastx.64 (Q9H6Y7) CDNA: FLJ21676 FIS, Q9H6Y7 82% 264 608 CLONECOL09164. HODAV25 787471 2282 WUblastx.64 (Q9UHS9) PRO1914 PROTEIN.Q9UHS9 100% 72 1 HODAW64 840069 2283 WUblastx.64 (Q9H7T2) CDNA FLJ14295FIS, Q9H7T2 93% 634 1263 CLONE PLACE1008426, WEAKLY SIMILAR TO RESHODAY17 806341 2284 WUblastx.64 (Q9H7L0) FLJ00062 PROTEIN Q9H7L0 90% 4921478 (FRAGMENT). 100% 77 487 HODBF86 605001 2289 WUblastx.64 (Q9BRM8)UNKNOWN (PROTEIN Q9BRM8 43% 189 410 FOR MGC: 13219). HODDJ25 824592 2299WUblastx.64 (Q9C0K7) AMYOTROPHIC Q9C0K7 100% 266 1519 LATERAL SCLEROSIS2. HODDQ06 834824 2302 WUblastx.64 (Q9NZK6) PDZ-BINDING KINASE. Q9NZK694% 200 1165 HODEA20 840376 2303 WUblastx.64 (Q9BXY9) RALBP1. Q9BXY9 84%141 1229 68% 6 179 HOEBI94 795312 2306 WUblastx.64 (Q9Y4J5)RIBONUCLEOPROTEIN Q9Y4J5 74% 823 999 (HNRNP 2H9). 100% 695 820 33% 710820 100% 167 469 HOEBJ70 836143 2307 WUblastx.64 (AAH09229) Unknown(protein for AAH09229 100% 560 646 MGC: 16480). HOECB33 840378 2308WUblastx.64 (Q9H6D8) CDNA: FLJ22362 FIS, Q9H6D8 100% 10 525 CLONEHRC06544. HOECX21 842866 2309 WUblastx.64 (Q9HC05) CD003 PROTEIN. Q9HC05100% 368 225 HOEDE27 825262 2310 WUblastx.64 (Q9P195) PRO1722. Q9P19555% 914 759 67% 780 649 HOEEK81 844390 2311 WUblastx.64 (BAB22091) Adultmale kidney BAB22091 60% 51 596 cDNA, RIKEN full-lengt HOEEZ62 6388332312 WUblastx.64 (Q9T9V8) NADH Q9T9V8 88% 66 173 DEHYDROGENASE SUBUNIT3. 83% 303 338 HOEFJ26 847422 2313 WUblastx.64 (Q9H5R3) CDNA: FLJ23147FIS, Q9H5R3 77% 1198 995 CLONE LNG09295. HOFMF63 847423 2315 WUblastx.64L6 surface protein - human pir|A42926|A42926 82% 409 690 77% 86 409HOFMJ65 664498 2316 WUblastx.64 (P70560) COLLAGEN ALPHA 1(XII) CA1C_RAT74% 987 1160 CHAIN (FRAGMENT). HOFMO16 596835 2318 HMMER PFAM: 3-betahydroxysteroid PF01073 68.3 149 346 2.1.1 dehydrogenase/isomerase familyWUblastx.64 (Q9BSN9) 3 BETA-HYDROXY- Q9BSN9 75% 11 184 DELTA5-C27-STEROID 83% 349 438 OXIDOREDUCTASE. 94% 290 346 HOFMV22 8128642321 WUblastx.64 (Q9P039) HSPC113. Q9P039 60% 180 293 50% 4 198 HOFNY15668259 2323 WUblastx.64 (Q9H9J2) CDNA FLJ12701 FIS, Q9H9J2 73% 69 326CLONE NT2RP1000730. 83% 331 999 HOFNY28 603911 2324 WUblastx.64interferon gamma receptor accessory pir|I38500|I38500 59% 13 654factor-1 precursor - human HOGAA41 843499 2326 WUblastx.64 (Q9D3B1)6330408J20RIK Q9D3B1 96% 580 1257 PROTEIN. HOGAB51 825278 2327WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, Q9H5R3 74% 919 1119 CLONELNG09295. HOGAH40 790978 2328 WUblastx.64 (Q9NX63) CDNA FLJ20420 FIS,Q9NX63 93% 185 844 CLONE KAT02462. HOGAP06 823364 2329 WUblastx.64(Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 70% 1445 1669 PROTEIN. HOGAR71722242 2331 HMMER PFAM: PMP-22/EMP/MP20/Claudin PF00822 336 96 632 2.1.1family WUblastx.64 (O95471) CLAUDIN-7. CLD7_HUMAN 100% 87 719 HOGCC26834792 2332 WUblastx.64 (Q9HCN4) XPA BINDING PROTEIN Q9HCN4 87% 191140 1. HOGCD78 610217 2333 WUblastx.64 (Q9H6Q7) CDNA: FLJ21979 FIS,Q9H6Q7 95% 428 487 CLONE HEP06065 (FRAGMENT). 100% 217 321 HOGCK03847427 2334 WUblastx.64 (Q99LE1) UNKNOWN (PROTEIN Q99LE1 53% 310 405 FORMGC: 7036). 78% 369 860 HOGCL01 846353 2335 HMMER PFAM: KOW motifPF00467 40.2 332 442 2.1.1 WUblastx.64 (Q96A35) Similar to mitochondrialQ96A35 100% 167 814 ribosomal protein L24. HOHBB36 847428 2336WUblastx.64 myosin I alpha chain - mouse pir|A45438|A45438 90% 2093 393% 2237 2103 HOHBC57 813392 2337 WUblastx.64 (Q9VEL9) CG4090 PROTEIN.Q9VEL9 21% 2162 1767 22% 4081 3632 31% 1961 1836 18% 2582 1737 17% 47724509 20% 1793 1374 20% 2582 2376 26% 1897 1652 21% 3583 2564 22% 35502534 21% 2087 1809 24% 1970 1704 22% 4084 2534 38% 575 498 20% 2021 177321% 3556 2534 HOHBO66 853375 2338 WUblastx.64 (Q9NY61) DED PROTEINQ9NY61 94% 1322 828 (APOPTOSIS ANTAGONIZING 88% 844 212 TRANSCRIPTIONFACTOR). HONAH67 821419 2342 WUblastx.64 (Q9H7T6) CDNA FLJ14272 FIS,Q9H7T6 97% 1192 1338 CLONE PLACE1004793, WEAKLY 96% 513 1172 SIMILAR TORET HOOAC84 604043 2343 WUblastx.64 (Q9UPN3) ACTIN CROSS-LINKINGACF7_HUMAN 84% 1324 1482 FAMILY PROTEIN 7 100% 325 444 (MACROPHIN) (100% 592 690 29% 1381 1461 36% 1387 1461 HOPBP13 825243 2344 WUblastx.64(Q9P195) PRO1722. Q9P195 63% 2105 1851 HORBI80 877660 2346 WUblastx.64(Q9NY33) DIPEPTIDYL- DPP3_HUMAN 100% 30 92 PEPTIDASE III (EC 3.4.14.4)(DPP 99% 92 2239 III) ( HORBL77 852099 2347 WUblastx.64 (Q9CWX4)2410001E19RIK Q9CWX4 27% 852 1034 PROTEIN. 31% 212 784 HOSEM81 8463542350 WUblastx.64 (O75872) RAB3-GAP O75872 100% 1012 803 REGULATORYDOMAIN. HOSEO83 847083 2351 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 68% 356 412 CLONE KAIA0536. 73% 310 354 53% 551 769 HOSFR35845994 2352 WUblastx.64 (Q9NXV7) CDNA FLJ20035 FIS, Q9NXV7 63% 9 320CLONE COL00213. 67% 316 780 HOUBC29 872565 2354 WUblastx.64 GTP-bindingprotein rab2 - rat pir|B39963|B39963 94% 763 876 HOUBG39 601696 2355WUblastx.64 (Q9H6G8) CDNA: FLJ22294 FIS, Q9H6G8 79% 1603 1403 CLONEHRC04426. HOUCD12 605006 2356 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS,Q9H728 69% 250 555 CLONE COL04765. HOUDB17 603417 2357 WUblastx.64(Q9N083) UNNAMED PORTEIN Q9N083 66% 672 367 PRODUCT. HOUIG68 793749 2363WUblastx.64 (Q9NVC9) CDNA FLJ10808 FIS, Q9NVC9 100% 2 355 CLONENT2RP4000879, WEAKLY SIMILAR TO UBI HOVAJ68 741098 2369 WUblastx.64(Q9HA67) CDNA FLJ12155 FIS, Q9HA67 55% 1588 1421 CLONE MAMMA1000472.HOVAW46 892162 2370 WUblastx.64 (O00363) PUTATIVE P150. O00363 41% 395345 39% 1030 773 37% 1359 1009 71% 759 697 45% 697 359 HOVBB19 8437682371 WUblastx.64 catalase (EC 1.11.1.6) - pir|I40767|I40767 97% 307 197Campylobacter jejuni HOVBI16 581097 2374 WUblastx.64 (AAG50170)Tripartite motif protein AAG50170 63% 83 115 TRIM28 alpha. 83% 202 702HOVCO53 564632 2380 WUblastx.64 (Q9H8N2) CDNA FLJ13381 FIS, Q9H8N2 52%1321 1127 CLONE PLACE1001010. HPBDE33 853660 2384 WUblastx.64hypothetical protein pir|T12458|T12458 64% 257 985 DKFZp564O0823.1 -human HPBDE33 897372 2385 WUblastx.64 hypothetical proteinpir|T12458|T12458 65% 257 985 DKFZp564O0823.1 - human HPCAG17 7578362387 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, Q9H743 64% 1306 1013 CLONECOL03536. HPCAG17 863943 2388 WUblastx.64 (Q9H387) PRO2550. Q9H387 71%1141 1007 71% 1008 850 HPDDQ28 566793 2391 WUblastx.64 (O95357) PUTATIVEG PROTEIN- O95357 98% 231 440 COUPLED RECEPTOR (CDNA 100% 10 231FLJ10899 FIS, CLON HPDDT14 580867 2392 WUblastx.64 (Q9BGV8) HYPOTHETICAL10.0 KDA Q9BGV8 71% 193 5 PROTEIN. HPFCP75 581083 2399 WUblastx.64(Q9NX17) CDNA FLJ20489 FIS, Q9NX17 53% 656 949 CLONE KAT08285. HPFDB66829318 2400 WUblastx.64 (Q9NTM9) BA483F11.3 (CGI-32 Q9NTM9 100% 102 920PROTEIN). HPFDD28 824856 2401 WUblastx.64 (Q9P195) PRO1722. Q9P195 66%672 628 70% 622 551 69% 815 660 HPIAK27 852658 2404 WUblastx.64(AAH06621) RIKEN cDNA AAH06621 83% 16 1050 2810403A07 gene. 70% 12861864 95% 1162 1293 40% 1162 1290 34% 1201 1269 44% 1174 1245 HPIAL55847429 2405 WUblastx.64 (Q9D0W4) 1110060O18RIK Q9D0W4 96% 506 592PROTEIN. 90% 1088 1150 72% 694 1002 100% 82 231 90% 1778 1807 HPIAT18877663 2406 WUblastx.64 (Q9H397) PRO2852. Q9H397 84% 3823 3728 74% 37353571 HPIAZ52 801924 2407 WUblastx.64 (Q9H387) PRO2550. Q9H387 68% 20821987 67% 1988 1833 HPIBA07 886191 2408 WUblastx.64 (Q99ML9) ARKADIA.Q99ML9 73% 61 1482 HPIBA24 840379 2409 WUblastx.64 (Q9ULZ5) GONADOTROPINQ9ULZ5 50% 27 1865 INDUCIBLE TRANSCRIPTION 56% 378 1793 REPRESSOR-4. 57%420 1805 53% 549 1868 53% 330 1544 HPIBI40 588944 2410 WUblastx.64(O43264) ZW10_HUMAN 99% 1 339 CENTROMERE/KINETOCHORE 98% 336 860 PROTEINZW10 HOMOLOG. HPJAB75 841653 2413 WUblastx.64 (Q9BZ63) FKSG60. Q9BZ6380% 1581 1273 HPJAN76 826185 2414 WUblastx.64 (O43194) PUTATIVE GPROTEIN- GP39_HUMAN 89% 328 828 COUPLED RECEPTOR GPR39. HPJAN76 8548932415 WUblastx.64 (O43194) PUTATIVE G PROTEIN- GP39_HUMAN 89% 328 828COUPLED RECEPTOR GPR39. HPJAU94 826719 2416 WUblastx.64 (O00371) L1ELEMENT L1.21 P40 O00371 83% 3944 4159 PROTEIN. 56% 3529 3921 HPJAW78812766 2417 WUblastx.64 (Q9D1W2) C030013D06RIK Q9D1W2 44% 87 254PROTEIN. 38% 96 266 40% 77 262 45% 87 260 47% 86 256 43% 243 85 40% 25986 39% 249 67 41% 261 88 HPJBS16 608307 2418 WUblastx.64 (CAC39435)Epigen protein precursor. CAC39435 64% 31 357 HPJBU04 798101 2419WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, Q9H743 72% 830 567 CLONECOL03536. 47% 2315 2265 HPJCP75 886192 2421 WUblastx.64 (Q9GMX5)HYPOTHETICAL 12.9 KDA Q9GMX5 61% 1459 1704 PROTEIN. HPJCV35 827317 2422WUblastx.64 (Q9Y5S2) CDC42-BINDING Q9Y5S2 92% 2685 2951 PROTEIN KINASEBETA. 100% 533 610 HPJCX13 852869 2423 HMMER PFAM: Reverse transcriptase(RNA- PF00078 307.8 3321 4148 2.1.1 dependent DNA polymerase)WUblastx.64 hypothetical protein (L1H 3′ region) - pir|B34087|B34087 96%4105 266 human HPMBT05 658715 2427 WUblastx.64 (Q14287) HYPOTHETICALQ14287 73% 491 592 PROTEIN (FRAGMENT). 85% 403 483 HPMDD27 830748 2432WUblastx.64 (Q9NZX0) HSPC068. Q9NZX0 96% 2 1417 HPMDF45 638148 2433WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 67% 1678 1857 CLONEKAIA0536. 72% 1856 1987 HPMDP57 567303 2434 WUblastx.64 (Q9H387)PRO2550. Q9H387 64% 1286 1074 77% 1447 1211 HPMEG72 795709 2435WUblastx.64 (O00549) ORF2-LIKE PROTEIN O00549 55% 1844 2056 (FRAGMENT).HPMFM70 756931 2436 WUblastx.64 (Q9H387) PRO2550. Q9H387 81% 2108 199861% 2286 2248 68% 2248 2105 HPMFP48 597457 2437 WUblastx.64 (Q9P195)PRO1722. Q9P195 66% 987 853 69% 1130 975 HPMFW01 844865 2438 WUblastx.64(Q9NP48) PUTATIVE LIPID Q9NP48 97% 973 1113 KINASE (CDNA FLJ10842 FIS,CLONE NT2RP4001343 HPMGW43 830452 2440 WUblastx.64 vesicle-associatedmembrane protein- pir|JG0186|JG0186 100% 31 72 associated protein B -human 95% 59 427 HPMKB09 900362 2442 WUblastx.64 (Q9UJU6) SRC HOMOLOGY 3Q9UJU6 92% 798 1406 DOMAIN-CONTAINING PROTEIN 92% 117 656 HIP-55(DREBRIN F). HPMSH26 780109 2443 WUblastx.64 (Q9NQC3) NOGO-A PROTEIN.Q9NQC3 69% 1592 1014 70% 1748 1578 HPMSH96 610023 2444 WUblastx.64(AAH00127) Glutathione-S- AAH00127 88% 1203 1505 transferase like,glutathi HPQAJ27 782957 2446 WUblastx.64 peptidyl-prolyl cis-transisomerase pir|B81216|B81216 54% 1370 987 NMB0281 [imported] - Neisseria77% 973 707 meningitidis (strain MC58 serogroup B) HPQAN50 788813 2447WUblastx.64 (O00549) ORF2-LIKE PROTEIN O00549 35% 381 10 (FRAGMENT). 32%1151 222 38% 1285 590 HPRAD30 805969 2458 WUblastx.64 (Q9P1C6) PRO2738.Q9P1C6 52% 2465 2265 HPRCC91 638151 2459 WUblastx.64 (Q9H1R7) BA534G20.4Q9H1R7 100% 2 97 (SUPERVILLIN) (FRAGMENT). HPRCF40 834808 2460WUblastx.64 (AAH07482) Similar to conserved AAH07482 97% 3 221 membraneprotein at HPRCF50 638153 2461 WUblastx.64 (Q9H387) PRO2550. Q9H387 66%1787 1912 58% 1614 1790 HPRCM72 813512 2463 WUblastx.64 (Q9D3K9)2810468K05RIK Q9D3K9 45% 296 526 PROTEIN. HPRCS59 601523 2464WUblastx.64 (Q61787) ORF 2. Q61787 30% 746 189 HPRCT73 610024 2465WUblastx.64 (Q9NPZ5) B3G2_HUMAN 96% 1231 1145 GALACTOSYLGALACTOSYLXYL89% 1476 1300 OSYLPROTEIN 3-BETA- GLUCURON HPTRE80 884167 2467WUblastx.64 (O43819) SCO2 PROTEIN SCO2_HUMAN 85% 779 39 HOMOLOGPRECURSOR. HPTRI42 655362 2468 WUblastx.64 (Q9BVA7) UNKNOWN (PROTEINQ9BVA7 85% 3 611 FOR MGC: 5621). HPTTT62 561954 2473 WUblastx.64(Q9H3X5) HYPOTHETICAL 85.5 KDA Q9H3X5 100% 8 169 PROTEIN (FRAGMENT).HPTVH24 831983 2474 WUblastx.64 (Q9H7Z7) CDNA FLJ14038 FIS, Q9H7Z7 90% 3974 CLONE HEMBA1005206. HPTVI96 636064 2477 WUblastx.64 (Q9H5X3)HYPOTHETICAL 13.8 KDA Q9H5X3 77% 42 416 PROTEIN. HPVAA15 783074 2478WUblastx.64 (AAK54355) ATP-binding cassette AAK54355 40% 4 483transporter family 33% 7 477 31% 487 870 30% 487 828 HPWAS27 536008 2484WUblastx.64 (Q9P0E3) HSPC093 (FRAGMENT). Q9P0E3 40% 1042 1146 65% 512625 HPWAV82 830084 2486 WUblastx.64 (Q9H387) PRO2550. Q9H387 79% 3 8969% 104 229 HPWBA36 840380 2487 WUblastx.64 (Q9H387) PRO2550. Q9H387 54%1183 1073 51% 1238 1152 62% 1380 1219 HPWTF23 843700 2488 HMMER PFAM:TSC-22/dip/bun family PF01166 146.4 442 621 2.1.1 WUblastx.64 (Q99576)GLUCOCORTICOID- GILZ_HUMAN 94% 271 672 INDUCED LEUCINE ZIPPER PROTEIN(DEL HPWTF23 844775 2489 HMMER PFAM: TSC-22/dip/bun family PF01166 146.4442 621 2.1.1 WUblastx.64 (Q99576) GLUCOCORTICOID- GILZ_HUMAN 94% 271672 INDUCED LEUCINE ZIPPER PROTEIN (DEL HPWTF53 844737 2490 WUblastx.64(Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 48% 1855 2082 PROTEIN. HRAAC36798104 2494 WUblastx.64 (Q26195) PVA1 GENE. Q26195 65% 835 758 62% 750565 41% 2229 2119 HRAAF59 847086 2495 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 56% 1519 1247 CLONE COL04765. HRAAG89 621271 2496WUblastx.64 (Q9GMW5) HYPOTHETICAL 45.1 KDA Q9GMW5 93% 2 187 PROTEIN.HRAAZ12 834637 2498 WUblastx.64 (AAG41897) Neuropilin-2a(17). AAG41897100% 1361 1435 92% 863 901 56% 385 579 96% 579 878 79% 901 1356 HRABP28823344 2500 WUblastx.64 (AAK55521) PRO0764. AAK55521 44% 1136 975 44%1245 1111 HRABU56 621381 2501 WUblastx.64 (O75876) RNA-BINDING PROTEIN.O75876 90% 105 320 HRABZ80 562230 2502 WUblastx.64 (Q9H743) CDNA:FLJ21394 FIS, Q9H743 64% 1166 1116 CLONE COL03536. 54% 1104 1000 HRACB01637647 2503 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 52% 14231349 PROTEIN. 52% 1344 1135 HRACI39 840461 2504 WUblastx.64 (Q9N083)UNNAMED PORTEIN Q9N083 59% 1346 1146 PRODUCT. HRADU15 801926 2505WUblastx.64 (Q9H7S6) CDNA FLJ14310 FIS, Q9H7S6 75% 645 586 CLONEPLACE3000271. 74% 787 638 HRDAH04 651356 2506 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 38% 1336 1229 CLONE COL04765. 60% 1478 1329 HRDBA20637709 2507 WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, Q9HA67 80% 1113 1069CLONE MAMMA1000472. 71% 1049 1008 79% 1267 1106 HRDBD32 637710 2508WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, Q9HA67 80% 1113 1069 CLONEMAMMA1000472. 71% 1049 1008 79% 1267 1106 HRDBL01 631169 2509WUblastx.64 (Q9P195) PRO1722. Q9P195 65% 934 755 HRDDM85 799542 2510WUblastx.64 (O95662) POT. ORF VI O95662 60% 1034 1096 (FRAGMENT). 56%538 1077 HRDEJ86 695755 2512 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 74% 827 627 CLONE KAIA0536. HRDFE30 750872 2514 WUblastx.64(Q9NWU2) BA305P22.1. Q9NWU2 89% 533 823 95% 141 548 HRDFT83 606799 2515WUblastx.64 (O60448) NEURONAL THREAD O60448 60% 442 377 PROTEINAD7C-NTP. 84% 584 528 60% 439 380 53% 578 459 61% 932 768 30% 778 64168% 779 714 70% 942 769 58% 387 337 47% 948 892 42% 584 294 100% 691 66862% 948 664 HRGCA01 589970 2516 WUblastx.64 (Q9H387) PRO2550. Q9H387 57%1318 1016 HRGCA06 866189 2517 HMMER PFAM: Ribosomal protein S16 PF0088669.1 143 325 2.1.1 WUblastx.64 (Q9Y3D3) 28S RIBOSOMAL RT16_HUMAN 99% 74445 PROTEIN S16, MITOCHONDRIAL PRECURSOR HRGSE38 898233 2518 WUblastx.64ATPase inhibitor precursor, pir|JC7175|JC7175 83% 77 367 mitochondrial -human HRLME03 610614 2520 WUblastx.64 (Q9H3B9) PRO0956. Q9H3B9 39% 220122 68% 111 46 HROAP64 835467 2522 WUblastx.64 (Q24333) ELASTIN LIKEPROTEIN Q24333 100% 46 117 (FRAGMENT). HROAS35 827304 2523 WUblastx.64cytochrome-c oxidase (EC 1.9.3.1) pir|A00482|OTHU3 77% 483 881 chainIII - human 1 HROBJ10 836368 2525 WUblastx.64 (Q9Y5P3) RETINOIC ACID-RAI2_HUMAN 36% 1719 1441 INDUCED PROTEIN 2. 96% 1817 1719 96% 1054 671100% 1445 1044 HRTAE88 822964 2529 WUblastx.64 (Q13579) MARINER Q1357976% 2579 2845 TRANSPOSASE. HRTAP63 780698 2530 WUblastx.64 (Q9Y3C9)CGI-127 PROTEIN. Q9Y3C9 100% 498 860 HSAAN03 599334 2532 WUblastx.64(Q9H387) PRO2550. Q9H387 70% 924 832 72% 676 602 77% 1094 921 HSAAS05703244 2533 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 55% 1475 1416PRODUCT. 55% 1419 1216 HSAAW13 821334 2534 WUblastx.64 (AAK57641)CAMP-specific cyclic AAK57641 99% 1 1101 nucleotide phosphod HSATA61801927 2538 WUblastx.64 (Q9CR30) 1110007C05RIK Q9CR30 73% 6 224 PROTEIN.HSATG66 824903 2539 WUblastx.64 (Q9JKP5) MUSCLEBLIND. Q9JKP5 100% 561590 52% 13 213 83% 1 465 HSATI91 838829 2540 WUblastx.64 hypotheticalprotein (L1H 3′ region) - pir|B34087|B34087 43% 345 127 human 35% 808515 30% 828 580 50% 527 375 32% 128 45 HSATR50 826398 2541 WUblastx.64(AAH02742) U6 snRNA-associated AAH02742 100% 397 483 Sm-like proteinLSm8 HSATT82 566784 2542 WUblastx.64 (Q9HAD8) CDNA FLJ11786 FIS, Q9HAD857% 1004 891 CLONE HEMBA1006036. 68% 915 766 HSATW19 637658 2543WUblastx.64 (Q9UI50) PRO0657 (FRAGMENT). Q9UI50 75% 448 669 HSATW67604938 2544 WUblastx.64 pro-pol-dUTPase polyprotein - murinepir|T29097|T29097 63% 653 441 endogenous retrovirus ERV-L 82% 436 119(fragment) HSATZ02 490895 2545 WUblastx.64 (Q9H387) PRO2550. Q9H387 75%964 857 76% 858 742 HSAUB89 600369 2547 WUblastx.64 (Q9BGW3)HYPOTHETICAL 13.5 KDA Q9BGW3 62% 359 631 PROTEIN. HSAUI53 866191 2548WUblastx.64 retrovirus-related reverse transcriptase pir|B25313|GNLRL142% 362 9 pseudogene - slow loris 32% 562 365 44% 942 868 44% 1037 95738% 570 436 37% 827 723 HSAUV74 866193 2549 WUblastx.64 (Q9UHT1) PRO1902PROTEIN. Q9UHT1 62% 827 693 HSAUX39 823161 2550 WUblastx.64 (Q62510)ZINC FINGER PROTEIN Q62510 33% 960 1040 62 (FRAGMENT). 41% 1319 1645 43%1244 1975 50% 1343 1975 52% 1349 1894 59% 1412 1975 45% 1235 1975 63%1385 1972 52% 1349 1966 63% 1388 1966 48% 1130 1810 49% 1244 1975 64%1367 1972 56% 1223 1975 HSAVE52 600370 2552 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 55% 1425 1366 CLONE COL04765. 56% 1384 1127 HSAVH32603367 2553 WUblastx.64 (AAK55521) PRO0764. AAK55521 73% 811 767 56% 789547 HSAVO11 566467 2555 WUblastx.64 (O60448) NEURONAL THREAD O60448 41%1599 1207 PROTEIN AD7C-NTP. 66% 1597 1439 54% 1257 1192 64% 1582 1301HSAVO17 738007 2556 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, Q9H743 72%1407 1129 CLONE COL03536. HSAVQ13 606818 2557 WUblastx.64 (Q9GMX5)HYPOTHETICAL 12.9 KDA Q9GMX5 66% 494 538 PROTEIN. 72% 406 471 HSAVR85786185 2558 WUblastx.64 (Q9H396) PRO2870. Q9H396 100% 3791 3546 HSAVY92606808 2559 WUblastx.64 (Q9H5T7) CDNA: FLJ23054 FIS, Q9H5T7 100% 19 123CLONE LNG03193. HSAVZ05 690151 2560 WUblastx.64 (Q9H743) CDNA: FLJ21394FIS, Q9H743 65% 57 257 CLONE COL03536. 56% 256 303 67% 1529 1212 HSAWB58738018 2561 WUblastx.64 (Q9BGV8) HYPOTHETICAL 10.0 KDA Q9BGV8 75% 13861607 PROTEIN. HSAWH36 581087 2562 WUblastx.64 (Q9NX17) CDNA FLJ20489FIS, Q9NX17 71% 1109 867 CLONE KAT08285. HSAWM20 606840 2563 WUblastx.64(Q9P147) PRO2822. Q9P147 67% 488 387 57% 363 322 73% 591 490 HSAWM74866195 2564 WUblastx.64 (O95166) MM46 (HT004 PROTEIN) O95166 100% 8 85(MAP1 LIGHT CHAIN 3 RELATED PROTEIN). HSAWX70 872498 2565 WUblastx.64(O00369) L1 ELEMENT L1.20 P40 O00369 43% 1309 1088 PROTEIN. 73% 1028 300HSAXI10 598726 2567 WUblastx.64 (Q9H387) PRO2550. Q9H387 79% 643 512 75%811 776 71% 776 621 HSAXL49 606826 2568 WUblastx.64 (Q9H387) PRO2550.Q9H387 63% 742 572 83% 863 717 HSAXL82 566801 2569 WUblastx.64 (Q9CXK1)5730406I15RIK Q9CXK1 96% 533 613 PROTEIN. HSAXS06 668260 2572WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS, Q9H743 50% 955 824 CLONECOL03536. 62% 1121 954 HSAYL24 608642 2574 WUblastx.64 (Q9UI59) PRO0478PROTEIN. Q9UI59 73% 132 7 HSBAJ47 842694 2578 WUblastx.64 (Q9H189)SPHINGOSINE-1- Q9H189 100% 1 237 PHOSPHATASE. HSDDC55 663277 2580WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 82% 743 793 CLONEKAIA0536. 57% 490 741 HSDEA26 822812 2581 WUblastx.64 (Q9UHT1) PRO1902PROTEIN. Q9UHT1 76% 1325 1387 75% 1140 1322 HSDGH56 853379 2587WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 94% 865 815 CLONECOL04765. 61% 1096 1058 70% 1058 879 HSDGM01 608310 2588 WUblastx.64(Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 85% 722 781 PROTEIN. 53% 529 726HSDGM42 870143 2589 WUblastx.64 (Q9BT21) SIMILAR TO RIKEN Q9BT21 92% 3602639 CDNA 2610005L19 GENE (FRAGMENT). HSDGM42 824916 2590 WUblastx.64(Q9BT21) SIMILAR TO RIKEN Q9BT21 91% 359 2638 CDNA 2610005L19 GENE(FRAGMENT). HSDGM42 852473 2591 WUblastx.64 (Q9BT21) SIMILAR TO RIKENQ9BT21 95% 1544 606 CDNA 2610005L19 GENE (FRAGMENT). HSDGM42 861925 2592WUblastx.64 (Q9BT21) SIMILAR TO RIKEN Q9BT21 92% 420 2699 CDNA2610005L19 GENE (FRAGMENT). HSDGM42 865828 2593 WUblastx.64 (Q9BT21)SIMILAR TO RIKEN Q9BT21 92% 420 2699 CDNA 2610005L19 GENE (FRAGMENT).HSDGM42 886748 2594 WUblastx.64 (Q9BT21) SIMILAR TO RIKEN Q9BT21 92% 4202699 CDNA 2610005L19 GENE (FRAGMENT). HSDIK31 847087 2597 WUblastx.64(O15121) PUTATIVE FATTY ACID O15121 100% 19 369 DESATURASE MLD 97% 354881 (DEGENERATIVE SPERMATOCYT HSDJC96 753284 2599 WUblastx.64 (Q9Y6A3)HYPOTHETICAL 5.6 KDA Q9Y6A3 100% 1946 1800 PROTEIN (FRAGMENT). HSDJF04695756 2601 WUblastx.64 (O95890) UNKNOWN. O95890 94% 2 382 HSDJG47847325 2602 WUblastx.64 (Q9H6U6) CDNA: FLJ21857 FIS, Q9H6U6 84% 59 1180CLONE HEP02294. HSDJH72 805971 2603 WUblastx.64 (Q9BVD9) UNKNOWN(PROTEIN Q9BVD9 66% 1500 1447 FOR MGC: 5149). 71% 1709 1485 HSDJL07895387 2604 WUblastx.64 (Q9H5R3) CDNA: FLJ23147 FIS, Q9H5R3 64% 764 898CLONE LNG09295. 82% 1481 1290 HSDJR49 741079 2605 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 63% 1000 1122 CLONE COL04765. 70% 893 101568% 786 872 62% 1124 1210 73% 1000 1044 67% 569 733 HSDJV24 806246 2606WUblastx.64 (Q9CWT1) 2410004N11RIK Q9CWT1 72% 539 1429 PROTEIN. HSDJV40623716 2607 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 69% 1105 977CLONE KAIA0536. 59% 1360 1295 38% 1583 1401 60% 1277 1104 HSDKA64 6003722608 WUblastx.64 (Q9H387) PRO2550. Q9H387 80% 1340 1278 72% 1548 1342HSDKF96 839730 2610 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 63% 16721412 PRODUCT. HSDZO08 827460 2611 WUblastx.64 (Q9UES6) I-1 RECEPTORQ9UES6 74% 1 393 CANDIDATE PROTEIN. 30% 1 156 92% 449 1648 HSEBB18877813 2613 WUblastx.64 (Q9NXX4) CDNA FLJ20005 FIS, Q9NXX4 89% 476 898CLONE ADKA02526. HSFAM19 691371 2614 WUblastx.64 (O18966) EAG CHANNEL.O18966 83% 76 510 HSHAG54 834781 2615 WUblastx.64 (Q9H5R3) CDNA:FLJ23147 FIS, Q9H5R3 51% 1028 738 CLONE LNG09295. HSHAS72 835991 2616HMMER PFAM: G-protein gamma subunit. PF00631 139.1 225 422 2.1.1WUblastx.64 (AAK53385) G protein gamma 12 AAK53385 100% 207 422 subunit.HSHAX04 812178 2617 WUblastx.64 peptidylprolyl isomerase (EC 5.2.1.8)pir|S66681|S66681 96% 14 916 A - human HSHBT15 581088 2618 WUblastx.64(O95863) ZINC FINGER PROTEIN SNAI_HUMAN 100% 570 680 SNAI1 (SNAILPROTEIN 79% 10 570 HOMOLOG) HSHCE85 855969 2619 WUblastx.64 (Q9Y546)DJ167A19.4 (NOVEL Q9Y546 100% 202 1224 PROTEIN). HSIAC81 783076 2620WUblastx.64 (Q9H3T4) KLOTHO-RELATED Q9H3T4 99% 8 1261 PROTEIN 1. HSIAP01897538 2622 WUblastx.64 (Q9NXP8) CDNA FLJ20124 FIS, Q9NXP8 92% 590 673CLONE COL06056. 28% 218 535 100% 685 732 89% 71 613 HSIDZ25 658721 2625WUblastx.64 (Q9HBN2) HYPOTHETICAL 15.8 KDA Q9HBN2 37% 1366 1280 PROTEIN.80% 1689 1597 HSIEB64 651359 2626 WUblastx.64 (Q9P1J1) PRO1546. Q9P1J170% 1718 1747 60% 1860 1949 53% 1741 1875 HSIFO61 845026 2628WUblastx.64 (O95831) PROGRAMED CELL PCD8_HUMAN 96% 95 1933 DEATH PROTEIN8, MITOCHONDRIAL PREC HSIFO61 852715 2629 WUblastx.64 (O95831) PROGRAMEDCELL PCD8_HUMAN 96% 183 2021 DEATH PROTEIN 8, MITOCHONDRIAL PREC HSIGC63877486 2630 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 58% 1734 1354CLONE KAIA0536. HSIGM95 840382 2631 WUblastx.64 (Q9H397) PRO2852. Q9H39780% 818 759 75% 754 707 77% 942 823 HSJAN83 825132 2633 WUblastx.64(Q9HAD8) CDNA FLJ11786 FIS, Q9HAD8 86% 1063 977 CLONE HEMBA1006036. 63%963 898 57% 827 771 87% 839 768 77% 960 841 HSJAQ10 853383 2634WUblastx.64 (AAH05957) Solute carrier family 25 AAH05957 100% 11 187(mitochondrial HSJAR59 846364 2635 WUblastx.64 (Q9NZS6) GLUCOCORTICOIDQ9NZS6 100% 16 138 RECEPTOR AF-1 SPECIFIC ELONGATION FACTOR (FRA HSJAU93702019 2636 WUblastx.64 (Q9BUK4) SIMILAR TO Q9BUK4 74% 123 728HYPOTHETICAL PROTEIN FLJ10709. HSKHV81 841590 2646 WUblastx.64 (Q9HA67)CDNA FLJ12155 FIS, Q9HA67 60% 935 801 CLONE MAMMA1000472. 26% 308 219HSKYR49 806548 2648 WUblastx.64 (Q9BTV7) UNKNOWN (PROTEIN Q9BTV7 100% 10456 FOR IMAGE: 3357127) (FRAGMENT). HSKYU81 899335 2649 WUblastx.64(Q9Y2W2) SH3 DOMAIN-BINDING Q9Y2W2 84% 950 1276 PROTEIN SNP70(NPW38-BINDING 100% 536 565 PROTEIN NPWB 31% 240 365 72% 6 533 HSKYY92853384 2650 WUblastx.64 (Q9P0E3) HSPC093 (FRAGMENT). Q9P0E3 57% 14551351 50% 1348 1193 HSLAB11 823825 2651 WUblastx.64 (Q9CVT0)1700040C17RIK Q9CVT0 99% 915 1427 PROTEIN (FRAGMENT). 34% 313 453 89%187 915 HSLAS96 740764 2652 WUblastx.64 (Q9H387) PRO2550. Q9H387 62%1173 1075 73% 1378 1175 HSLAW59 637669 2653 WUblastx.64 (Q9HAD8) CDNAFLJ11786 FIS, Q9HAD8 52% 578 423 CLONE HEMBA1006036. 70% 427 287 HSLCH54562018 2654 WUblastx.64 (P51805) PLEXIN A3 PRECURSOR PLX4_HUMAN 97% 445570 (PLEXIN 4) (TRANSMEMBRANE 81% 9 446 PROT HSLCH57 899415 2655WUblastx.64 SREBP cleavage activating protein - pir|T18526|T18526 92%1408 2205 Chinese hamster 39% 658 774 47% 352 459 HSLCI86 737626 2656WUblastx.64 estrogen sulfotransferase (EC 2.8.2.—) - pir|JC2229|JC222933% 493 555 human 100% 704 1090 HSLCS31 604046 2657 HMMER PFAM: PPRrepeat PF01535 22.6 493 597 2.1.1 WUblastx.64 (Q9H9R0) CDNA FLJ12598FIS, Q9H9R0 98% 454 828 CLONE NT2RM4001384. 100% 826 1047 HSLCS34 7513242658 WUblastx.64 (Q9NVE5) CDNA FLJ10785 FIS, Q9NVE5 70% 40 576 CLONENT2RP4000457, WEAKLY 86% 375 1007 SIMILAR TO UBI HSLCV16 772948 2659WUblastx.64 (Q9H0J7) HYPOTHETICAL 53.4 KDA Q9H0J7 99% 1 552 PROTEIN. 87%1537 1698 HSLDW54 853386 2660 WUblastx.64 probable polpolyprotein-related pir|S21348|S21348 52% 732 631 protein 4 - rat 44%625 452 34% 1115 738 HSLEC18 722249 2661 WUblastx.64 (Q96RP7)Galbetal-3GalNAc 3′- Q96RP7 97% 60 1319 sulfotransferase. HSLEG59 6376712662 WUblastx.64 (Q14287) HYPOTHETICAL Q14287 44% 968 807 PROTEIN(FRAGMENT). 20% 745 614 50% 1150 941 HSLFR59 853388 2663 WUblastx.64hypothetical protein pir|T46471|T46471 86% 877 987 DKFZp434L0130.1 -human 93% 987 1481 HSLGD91 883491 2664 WUblastx.64 (Q9NX85) CDNAFLJ20378 FIS, Q9NX85 70% 764 817 CLONE KAIA0536. 72% 816 926 HSNAQ52600402 2672 WUblastx.64 (Q9BGZ4) HYPOTHETICAL 11.6 KDA Q9BGZ4 85% 197156 PROTEIN. 81% 142 95 HSNAW06 580248 2674 WUblastx.64 (Q9GMI2)HYPOTHETICAL 9.4 KDA Q9GMI2 61% 219 413 PROTEIN. HSNBQ36 784994 2678WUblastx.64 (Q9NUU5) CDNA FLJ11128 FIS, Q9NUU5 98% 358 732 CLONEPLACE1006236. HSNBS39 617125 2679 WUblastx.64 retrovirus-relatedhypothetical protein pir|S23650|S23650 76% 313 263 II - human 1 47% 8226 38% 275 93 HSOAT44 847357 2681 WUblastx.64 (Q9GZY9) CDNA: FLJ20877FIS, Q9GZY9 100% 10 195 CLONE ADKA02965 (CDNA: FLJ20871 FIS, CLO HSOBH11794000 2683 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 58% 657743 PROTEIN. 59% 508 603 HSOBW65 778388 2685 WUblastx.64 (Q14288)HYPOTHETICAL Q14288 64% 160 110 PROTEIN (FRAGMENT). 67% 636 142 HSPAA89825099 2686 WUblastx.64 (P05142) PROLINE-RICH PROTEIN PRP2_MOUSE 42% 210148 MP-2 PRECURSOR. 37% 1144 641 HSQBL20 780518 2696 WUblastx.64(Q9UBQ5) MRNA OF MUSCLE Q9UBQ5 100% 183 836 SPECIFIC GENE M9, COMPLETECDS (ARG134 PROTEI HSQCY74 886110 2698 WUblastx.64 (Q9H455) DJ383J4.4 (ANOVEL Q9H455 99% 10 1455 PROTEIN SIMILAR TO ASPARTYL-TRNA SYNTHETAHSRAA81 695759 2705 WUblastx.64 (CAC38441) DJ1033B10.5.1 (SAC2 CAC3844190% 9 749 (suppressor of actin 33% 596 694 100% 727 1086 HSRAO56 7198162706 WUblastx.64 (Q9HBS7) HYPOTHETICAL 14.2 KDA Q9HBS7 68% 1419 1324PROTEIN. 72% 1592 1416 HSRAV28 581102 2707 WUblastx.64 (Q9H387) PRO2550.Q9H387 61% 655 524 61% 823 785 75% 788 654 HSRDW57 562019 2709WUblastx.64 (BAB55068) CDNA FLJ14466 fis, BAB55068 100% 8 259 cloneMAMMA1000416. 91% 262 495 83% 485 520 HSREC72 601368 2710 WUblastx.64(Q9H387) PRO2550. Q9H387 88% 838 812 69% 783 625 HSREG42 839481 2711WUblastx.64 (Q9VZZ4) PXN PROTEIN. Q9VZZ4 47% 6 1484 HSRFD18 840771 2712WUblastx.64 (Q9H941) CDNA FLJ13033 FIS, Q9H941 100% 437 559 CLONENT2RP3001126. HSRGZ11 801929 2713 WUblastx.64 (Q9BYN8) DJ534B8.3 (NOVELQ9BYN8 100% 253 384 PROTEIN). HSRHB59 840384 2714 WUblastx.64 (Q9NWT0)HYPOTHETICAL 17.7 KDA Q9NWT0 100% 8 121 PROTEIN. 100% 123 308 HSSCC66559402 2716 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 65% 548 667PRODUCT. HSSEL28 838618 2721 WUblastx.64 (Q9P195) PRO1722. Q9P195 68%755 1042 HSSFP88 658726 2722 HMMER PFAM: Zinc finger, C3HC4 type PF0009736.1 828 953 2.1.1 (RING finger) WUblastx.64 (Q9H6Y7) CDNA: FLJ21676FIS, Q9H6Y7 90% 204 1133 CLONE COL09164. HSSGS62 741162 2723 WUblastx.64(Q9GMX5) HYPOTHETICAL 12.9 KDA Q9GMX5 60% 899 762 PROTEIN. 60% 200 141HSSJA23 847089 2724 WUblastx.64 (Q9BTH7) UNKNOWN (PROTEIN Q9BTH7 94% 272685 FOR MGC: 5601). 96% 1379 1561 HSSJF26 567431 2725 WUblastx.64(Q9HBS7) HYPOTHETICAL 14.2 KDA Q9HBS7 76% 600 689 PROTEIN. 46% 401 580HSSJM47 796096 2727 WUblastx.64 (Q9UJ98) STROMAL ANTIGEN 3, Q9UJ98 77%129 194 (STAG3). 75% 527 637 96% 899 994 HSSJW30 779822 2728 WUblastx.64(BAB55147) CDNA FLJ14580 fis, BAB55147 86% 2 46 clone NT2RM4001204. 92%45 488 HSSJW30 850566 2729 WUblastx.64 (BAB55147) CDNA FLJ14580 fis,BAB55147 67% 14 703 clone NT2RM4001204. HSSJW30 867721 2730 WUblastx.64(BAB55147) CDNA FLJ14580 fis, BAB55147 82% 672 842 clone NT2RM4001204.100% 625 675 89% 76 186 46% 131 220 60% 24 83 HSSMY35 740765 2731WUblastx.64 (Q9H7J9) FLJ00075 PROTEIN Q9H7J9 96% 20 217 (FRAGMENT).HSTAL93 841863 2732 WUblastx.64 (AAK52433) Low density lipoproteinAAK52433 98% 287 799 receptor-related 35% 284 787 35% 299 787 35% 287637 HSUAF06 863206 2734 WUblastx.64 pol polyprotein - Cas-Br-E murinepir|A26103|A26103 47% 630 944 leukemia virus (fragment) 50% 1194 1307HSUBX67 751266 2735 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 61% 624499 PRODUCT. 64% 766 608 HSUSB73 603912 2736 WUblastx.64 (Q9GMU5)HYPOTHETICAL 14.1 KDA Q9GMU5 57% 1158 1117 PROTEIN. 80% 130 56 HSVAC05836051 2737 WUblastx.64 (Q9H6G8) CDNA: FLJ22294 FIS, Q9H6G8 64% 688 539CLONE HRC04426. HSVBA83 812059 2742 WUblastx.64 (O60593)ARG/ABL-INTERACTING O60593 98% 313 516 PROTEIN ARGBP2B (FRAGMENT).HSVBY62 637113 2745 WUblastx.64 (Q9Y2Q7) HSPC005 PROTEIN Q9Y2Q7 100% 35217 (C11ORF10) (CHROMOSOME 11 OPEN READING FRAME HSXAI44 590743 2750WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 90% 1024 992 CLONECOL04765. 73% 1007 828 HSXAS59 838072 2752 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 85% 1515 1474 CLONE COL04765. 81% 1303 1256 62%1478 1305 HSXAY60 737753 2754 WUblastx.64 (Q9N032) UNNAMED PROTEINQ9N032 59% 1742 1602 PRODUCT. HSXCA83 830046 2756 WUblastx.64 (Q9UHD2)TANK BINDING Q9UHD2 39% 1121 1219 KINASE TBK1 (NF-KB- 98% 1215 1382ACTIVATING KINASE NAK). 93% 109 1197 HSXCX20 658728 2757 WUblastx.64(Q9BXA5) G-PROTEIN COUPLED Q9BXA5 100% 891 1049 RECEPTOR 91. 86% 61 942HSXFG21 805972 2758 WUblastx.64 (Q9CQQ2) 1700066F09RIK Q9CQQ2 47% 499933 PROTEIN (FRAGMENT). HSXFH82 699863 2759 WUblastx.64 (Q9MZZ7)HYPOTHETICAL 16.3 KDA Q9MZZ7 69% 1447 1611 PROTEIN. 92% 1124 1162 65%1146 1598 HSYBR79 873848 2761 WUblastx.64 vesicle-associated membraneprotein- pir|JG0186|JG0186 100% 193 861 associated protein B - humanHSYBV44 753253 2762 WUblastx.64 (Q9B2U5) ATP SYNTHASE 6. Q9B2U5 66% 84761 HSYBZ94 799543 2763 WUblastx.64 (Q9BZ73) NIR2. Q9BZ73 98% 2168 239299% 2388 2924 33% 1313 1399 33% 1895 1999 79% 21 2174 HT3AB13 8416802764 WUblastx.64 (Q9UP93) SHORT FORM Q9UP93 53% 663 980 TRANSCRIPTIONFACTOR C-MAF. 74% 271 612 HT4SB02 837688 2765 HMMER PFAM:emp24/gp25L/p24 family PF01105 231.4 78 521 2.1.1 WUblastx.64 proteintrafficking protein tmp21-I - pir|G01159|G01159 100% 84 524 human 100%21 74 HT4SB81 756723 2767 WUblastx.64 (O95621) TIC. O95621 95% 3 194 77%580 789 62% 185 631 41% 19 54 HT4SB81 844512 2768 WUblastx.64 (O95621)TIC. O95621 72% 185 790 95% 3 194 41% 19 54 57% 872 913 HT4SB81 8581542769 WUblastx.64 (O95621) TIC. O95621 71% 185 790 41% 19 54 95% 3 19457% 872 913 HTABF81 610040 2771 WUblastx.64 (Q9NRR3) NON-KINASE CDC42Q9NRR3 100% 48 299 EFFECTOR PROTEIN SPEC2. HTACX63 602694 2772WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 65% 919 860 CLONECOL04765. 78% 825 784 53% 1067 921 HTADC63 842131 2773 WUblastx.64(Q9D7U1) 2210407P13RIK Q9D7U1 40% 557 793 PROTEIN. 46% 162 557 HTADO61695760 2774 WUblastx.64 hypothetical protein pir|T42648|T42648 100% 9 95DKFZp434C1415.1 - human HTAEC59 846728 2776 WUblastx.64ubiquitin-conjugating enzyme pir|S53358|S53358 100% 409 591 E2.17 kB -rat 100% 156 383 HTAED89 801931 2777 HMMER PFAM: 7 transmembranereceptor PF00003 78.6 1240 1578 2.1.1 (metabotropic glutamate family)WUblastx.64 (O35363) CALCIUM SENSING O35363 51% 1590 1718 RECEPTOR,RELATED SEQUENCE 38% 858 920 2 (CALCIUM-SENSIN 38% 908 1171 53% 12161611 HTAEO35 732379 2780 WUblastx.64 (Q9H387) PRO2550. Q9H387 73% 14761195 HTDAF68 637685 2781 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H72872% 892 1041 CLONE COL04765. 50% 2 91 70% 711 890 HTDAI38 878930 2782WUblastx.64 (Q9NX73) CDNA FLJ20400 FIS, Q9NX73 88% 954 1268 CLONEKAT00587 (FRAGMENT). 30% 361 669 34% 1146 1874 37% 1314 1898 100% 343678 32% 930 1628 HTECE87 702025 2786 WUblastx.64 (Q9NVC3) CDNA FLJ10815FIS, Q9NVC3 100% 53 133 CLONE NT2RP4000989, WEAKLY 100% 133 279 SIMILARTO UNC HTEDF78 564215 2787 WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDAQ9BGW3 75% 1545 1423 PROTEIN. HTEDX05 862064 2789 WUblastx.64 (Q9D4H6)4932415A06RIK Q9D4H6 79% 16 441 PROTEIN. 86% 429 1649 HTEEC19 8620652790 WUblastx.64 translation initiation factor IF-2 pir|T43483|T43483100% 11 1321 homolog [similarity] - 1 HTEGH03 815562 2791 WUblastx.64(Q9UHB5) EPITHELIAL PROTEIN Q9UHB5 93% 32 928 LOST IN NEOPLASM ALPHA.HTEGH03 839477 2792 WUblastx.64 (Q9UHB5) EPITHELIAL PROTEIN Q9UHB5 82%678 845 LOST IN NEOPLASM ALPHA. 88% 1 732 HTEGY81 637689 2794WUblastx.64 (Q9CYN5) 5730405I09RIK Q9CYN5 74% 11 544 PROTEIN. HTEHB49823145 2796 WUblastx.64 (Q9H2T7) RANBP17. Q9H2T7 65% 126 254 99% 2031537 HTEHV60 637690 2798 WUblastx.64 (Q9D2H5) 4930486B16RIK Q9D2H5 88%72 1028 PROTEIN. 33% 153 281 89% 1027 1113 HTEHW80 862068 2799WUblastx.64 (Q9HAD8) CDNA FLJ11786 FIS, Q9HAD8 71% 297 578 CLONEHEMBA1006036. HTEID25 737852 2800 WUblastx.64 (Q9Y4V7) DJ1178H5.3 (NOVELQ9Y4V7 100% 259 384 PROTEIN) (FRAGMENT). HTEIJ23 784268 2801 WUblastx.64(Q9NX98) CDNA FLJ20363 FIS, Q9NX98 93% 107 1303 CLONE HEP17001. HTEIM62806472 2802 WUblastx.64 (Q9H3C1) PRO0872. Q9H3C1 81% 62 15 76% 123 61HTEIV33 603393 2803 WUblastx.64 hypothetical protein pir|T47135|T4713553% 259 11 DKFZp761L0812.1 - human (fragment) HTEJD61 828178 2807WUblastx.64 (BAB49394) Ml12208 protein. BAB49394 37% 437 682 27% 21 38030% 437 682 27% 9 383 24% 18 392 29% 21 386 32% 401 682 30% 138 395 24%452 682 27% 90 380 30% 395 679 28% 437 682 26% 392 592 30% 12 386HTEJL16 603409 2810 WUblastx.64 (Q9CPU8) 4921511D23RIK Q9CPU8 71% 453412 PROTEIN. 34% 1042 722 34% 1027 698 80% 412 257 32% 952 728 64% 1030596 HTEKD35 604979 2813 WUblastx.64 (Q9D6N1) CARBONIC Q9D6N1 89% 40 594ANHYDRASE (EC 4.2.1.1) (CARBONATE DEHYDRATASE). HTEKP82 694648 2814WUblastx.64 (Q9D9W1) 1700027A23RIK Q9D9W1 68% 147 689 PROTEIN. HTEKV69877673 2815 WUblastx.64 (Q9D400) 4933425K02RIK Q9D400 61% 157 1005PROTEIN. 66% 1052 1096 35% 52 210 HTFOB75 900824 2818 WUblastx.64(Q9BX86) HP95. Q9BX86 96% 162 2366 50% 2469 2675 21% 1857 2354 HTGAA35737945 2819 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 64% 1474 1349CLONE KAIA0536. 78% 1632 1465 HTGAD74 834464 2820 WUblastx.64 (Q9UHT1)PRO1902 PROTEIN. Q9UHT1 66% 665 621 67% 868 668 HTGAP05 637715 2821WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 65% 871 749 CLONEKAIA0536. 73% 990 868 HTGAR21 838159 2823 WUblastx.64 (Q9BVD9) UNKNOWN(PROTEIN Q9BVD9 80% 864 820 FOR MGC: 5149). 67% 1081 878 HTGAS70 8273202824 WUblastx.64 (AAH00037) DNA fragmentation AAH00037 95% 290 1216factor, 45 kD, alpha p HTGAT65 688864 2825 WUblastx.64 (Q9P0D8) HSPC098(FRAGMENT). Q9P0D8 42% 1074 1130 60% 1469 1573 HTGAU17 605125 2826WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 58% 621 692 PROTEIN.44% 703 876 HTGBK95 834490 2828 WUblastx.64 (Q9GMX5) HYPOTHETICAL 12.9KDA Q9GMX5 66% 126 55 PROTEIN. 70% 235 116 HTGCC01 598903 2829WUblastx.64 (Q9H387) PRO2550. Q9H387 73% 1099 962 68% 963 784 HTGCK43828867 2830 WUblastx.64 (P82914) 28S RIBOSOMAL RT15_HUMAN 91% 862 92PROTEIN S15, MITOCHONDRIAL PRECURSOR HTGDS43 605094 2831 WUblastx.64(O60921) HUS1+-LIKE PROTEIN. O60921 97% 706 831 HTGDS92 839478 2832WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 69% 1300 1001 CLONECOL04765. HTGEX34 877490 2833 WUblastx.64 (Q9H387) PRO2550. Q9H387 77%2277 1966 HTGGM37 827310 2835 WUblastx.64 (Q9NUM6) CDNA FLJ11267 FIS,Q9NUM6 76% 1781 1909 CLONE PLACE1009174. HTGGN22 782853 2836 WUblastx.64(Q9H5R3) CDNA: FLJ23147 FIS, Q9H5R3 57% 741 664 CLONE LNG09295. 66% 682524 HTHBC58 839916 2838 WUblastx.64 (Q9H387) PRO2550. Q9H387 80% 12671208 71% 1452 1294 HTHBQ29 561547 2840 WUblastx.64 (Q9BGV8) HYPOTHETICAL10.0 KDA Q9BGV8 78% 786 1010 PROTEIN. HTHBZ91 637697 2842 WUblastx.64(O60448) NEURONAL THREAD O60448 53% 823 668 PROTEIN AD7C-NTP. 61% 948802 69% 743 705 44% 458 273 52% 947 747 59% 594 466 61% 963 748 50% 360313 36% 891 802 39% 948 880 57% 569 324 50% 493 425 25% 848 561 48% 408289 26% 425 249 34% 454 272 30% 513 301 52% 588 367 HTHCA30 637124 2843WUblastx.64 (Q9BVD9) UNKNOWN (PROTEIN Q9BVD9 67% 627 466 FOR MGC: 5149).HTHDB20 669032 2845 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 79%426 355 CLONE COL04765. 60% 629 429 HTHDF45 621313 2846 WUblastx.64(Q9H387) PRO2550. Q9H387 42% 987 691 HTHDF86 815686 2847 WUblastx.64(Q9NX85) CDNA FLJ20378 FIS, Q9NX85 63% 1184 1249 CLONE KAIA0536. 83%1029 1193 50% 1495 1247 HTHDP65 637699 2849 WUblastx.64 (Q9H387)PRO2550. Q9H387 100% 42 16 66% 205 35 HTHDV50 789402 2851 WUblastx.64(Q9GMI7) HYPOTHETICAL 9.0 KDA Q9GMI7 47% 299 78 PROTEIN. HTJMA64 7751812852 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 75% 1065 1211 CLONECOL04765. 75% 1369 1500 52% 1209 1391 44% 1187 1267 64% 893 1087 HTLAD74638978 2854 WUblastx.64 (P78525) MYB PROTO-ONCOGENE P78525 48% 929 633PROTEIN (C-MYB). HTLAF81 855970 2855 WUblastx.64 (Q9BUS3) UNKNOWN(PROTEIN Q9BUS3 72% 306 1073 FOR IMAGE: 3461487) (FRAGMENT). HTLBF46839774 2856 HMMER PFAM: Papain family cysteine PF00112 255 176 751 2.1.1protease WUblastx.64 (Q9UBX1) CATHEPSIN F CATF_HUMAN 99% 56 757PRECURSOR (EC 3.4.22.41) (CATSF). HTLBF63 762847 2857 HMMER PFAM: MYNDfinger PF01753 53.8 652 762 2.1.1 WUblastx.64 (O75800) BLU PROTEIN.O75800 94% 10 792 HTLCX82 847091 2858 WUblastx.64 (Q9BTZ4) SIMILAR TOQ9BTZ4 100% 127 258 EXPRESSED SEQUENCE 2 72% 237 629 EMBRYONIC LETHAL(FRAGMENT). HTLDN34 866199 2860 WUblastx.64 (O94993) SOX30 PROTEIN.O94993 82% 242 751 89% 726 842 69% 9 137 HTLDP19 885353 2861 WUblastx.64(Q9D5P4) 4930403J07RIK PROTEIN. Q9D5P4 62% 530 751 84% 8 121 61% 159 581HTLEJ24 608317 2863 WUblastx.64 (Q9D7G6) 2310009N05RIK Q9D7G6 84% 2 619PROTEIN. HTLEJ75 815631 2864 WUblastx.64 (AAK52668) MMS19. AAK52668 92%31 2133 HTLEJ75 762849 2865 WUblastx.64 (BAB55315) CDNA FLJ14804 fis,BAB55315 85% 7 798 clone NT2RP4001638, w HTLEP55 637704 2866 WUblastx.64(AAL37611) Carboxypeptidase A5. AAL37611 97% 1242 1352 92% 1171 1251 53%561 656 100% 178 561 87% 608 1168 HTLEV80 866200 2867 WUblastx.64(O15020) BETA-SPECTRIN III O15020 100% 9 452 (FNTA III SPECTRIN).HTLEZ57 634874 2868 WUblastx.64 (Q9P195) PRO1722. Q9P195 57% 662 531 59%121 26 62% 481 401 HTLFA90 740770 2869 WUblastx.64 (Q9BRY0) UNKNOWN(PROTEIN Q9BRY0 100% 2 1072 FOR IMAGE: 2966557) (FRAGMENT). HTLGL33835020 2870 WUblastx.64 N-type calcium channel alpha-1 chain, 1pir|T45115|T45115 22% 364 1092 HTLGQ25 898114 2871 HMMER PFAM:Immunoglobulin domain PF00047 26.6 153 377 2.1.1 WUblastx.64 (Q9H106)DJ576H24.4 (NOVEL Q9H106 100% 114 443 PROTEIN MEMBER OF THE PTPNS(PROTEIN TYROS HTLGS72 897278 2872 WUblastx.64 (Q9JJC0) BRAIN CDNA,CLONE Q9JJC0 34% 6 563 MNCB-2717. HTLGY50 839479 2873 WUblastx.64(O73884) PUTATIVE O73884 39% 987 1100 PHOSPHATASE. 65% 589 1002 HTLHN86896930 2874 WUblastx.64 (BAB55144) CDNA FLJ14576 fis, BAB55144 95% 318938 clone NT2RM4001092, w HTLHN86 838287 2875 WUblastx.64 (BAB55144)CDNA FLJ14576 fis, BAB55144 95% 318 938 clone NT2RM4001092, w HTLHN86843766 2876 WUblastx.64 (BAB55144) CDNA FLJ14576 fis, BAB55144 95% 318938 clone NT2RM4001092, w HTLHN86 883351 2877 WUblastx.64 (BAB55144)CDNA FLJ14576 fis, BAB55144 95% 318 938 clone NT2RM4001092, w HTLIW29899417 2878 HMMER PFAM: Trypsin PF00089 226.4 133 852 2.1.1 WUblastx.64(Q9Y6M0) TESTISIN PRECURSOR TEST_HUMAN 100% 67 885 (EC 3.4.21.—)(EOSINOPHIL SERIN HTLJC15 898235 2879 WUblastx.64 (Q9D123) 1110032O16RIKQ9D123 71% 996 1715 PROTEIN. HTNAL14 886203 2880 WUblastx.64 (Q9NXU2)CDNA FLJ20054 FIS, Q9NXU2 100% 580 687 CLONE COL00849. HTNBJ15 8348722882 WUblastx.64 (Q9H055) HYPOTHETICAL 13.8 KDA Q9H055 99% 1536 1889PROTEIN. HTNBJ15 845783 2883 WUblastx.64 (Q9H055) HYPOTHETICAL 13.8 KDAQ9H055 99% 1536 1889 PROTEIN. HTNBJ15 853916 2884 WUblastx.64 (Q9H055)HYPOTHETICAL 13.8 KDA Q9H055 99% 1536 1889 PROTEIN. HTNBJ15 884024 2885WUblastx.64 (Q9H055) HYPOTHETICAL 13.8 KDA Q9H055 99% 1536 1889 PROTEIN.HTOAO58 855972 2889 WUblastx.64 (Q9GZW5) SCAN DOMAIN- Q9GZW5 49% 9741321 CONTAINING PROTEIN 2 (SCAND2). HTOAT56 702026 2890 WUblastx.64(AAH00407) Synaptogyrin 2. AAH00407 82% 425 673 83% 10 495 HTOBG07566862 2891 WUblastx.64 (Q9H288) SEROLOGICALLY Q9H288 100% 225 1343DEFINED BREAST CANCER 41% 498 1343 ANTIGEN NY-BR-16. 37% 438 1343 37%276 1187 33% 258 1319 34% 462 1304 30% 462 1286 50% 798 953 44% 11821343 66% 941 967 25% 261 839 39% 1098 1247 100% 42 71 HTOBG62 5668302892 WUblastx.64 (Q9H728) CDNA: FLJ21463 FIS, Q9H728 66% 1378 1112 CLONECOL04765. HTODO45 823125 2895 WUblastx.64 (AAH08373) Similar tohypothetical AAH08373 67% 1408 1226 protein PRO1722. HTOET03 845230 2899WUblastx.64 (Q9BQC3) SIMILAR TO Q9BQC3 83% 4 1041 DIPTHERIA TOXINRESISTANCE PROTEIN REQUIRED FOR D HTOET03 837213 2900 WUblastx.64(Q9BQC3) SIMILAR TO Q9BQC3 83% 4 1041 DIPTHERIA TOXIN RESISTANCE PROTEINREQUIRED FOR D HTOFA11 637719 2902 WUblastx.64 (Q30086) MHC CLASS IIHLA-DQ- Q30086 96% 1348 1635 ALPHA (DR2-DQW1/DR4 DQW3) 80% 1962 2069(FRAGMENT). 97% 694 942 68% 1882 1968 HTOFC33 824604 2903 WUblastx.64(Q9H387) PRO2550. Q9H387 65% 900 754 73% 1069 878 HTOGB79 762835 2904WUblastx.64 (O60448) NEURONAL THREAD O60448 52% 1639 1917 PROTEINAD7C-NTP. 60% 1642 1806 50% 1661 1825 31% 1465 1530 26% 1238 1528 27% 69227 60% 1854 1928 43% 1797 1865 32% 1420 1542 75% 2727 2596 52% 26062472 42% 1214 1137 77% 2727 2551 49% 2661 2500 42% 2663 2553 56% 12131166 45% 2715 2596 68% 1284 1219 41% 1302 1141 55% 1332 1273 48% 13321264 52% 2730 2674 55% 1333 1274 55% 1208 1155 60% 1339 1157 62% 27562478 HTOHE22 821698 2905 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX8575% 1008 1217 CLONE KAIA0536. HTOHG63 834832 2906 WUblastx.64 (Q9H8L6)CDNA FLJ13465 FIS, Q9H8L6 98% 2 670 CLONE PLACE1003493, WEAKLY SIMILARTO END HTOHJ93 762836 2907 WUblastx.64 (Q9H743) CDNA: FLJ21394 FIS,Q9H743 70% 1323 1048 CLONE COL03536. HTOHN40 843372 2910 WUblastx.64(Q9NX85) CDNA FLJ20378 FIS, Q9NX85 64% 1889 1839 CLONE KAIA0536. 50%1845 1654 HTOHR59 762850 2911 WUblastx.64 (AAH07609) Similar tohypothetical AAH07609 92% 1249 1127 protein PRO1722. HTOHS29 722256 2912WUblastx.64 (AAH08373) Similar to hypothetical AAH08373 80% 129 10protein PRO1722. HTOID65 636069 2913 WUblastx.64 (Q9H387) PRO2550.Q9H387 56% 630 761 50% 467 658 77% 1420 1316 78% 1314 1165 HTOIE17688061 2914 WUblastx.64 (Q9NWI4) CDNA FLJ20837 FIS, Q9NWI4 66% 942 889CLONE ADKA02602. 61% 1078 938 HTOIG16 845999 2915 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 93% 1558 1511 CLONE COL04765. 63% 1793 1563HTOIH39 839245 2916 WUblastx.64 (O60448) NEURONAL THREAD O60448 53% 7501106 PROTEIN AD7C-NTP. 46% 53 130 50% 1095 1184 51% 840 1049 57% 64 12656% 14 121 54% 987 1151 54% 29 133 40% 1039 1167 68% 19 93 HTOJB02600376 2918 WUblastx.64 (O60448) NEURONAL THREAD O60448 54% 780 652PROTEIN AD7C-NTP. 33% 1322 1143 50% 1275 1108 66% 919 770 47% 682 62652% 1235 1161 40% 889 770 50% 787 632 58% 816 727 41% 1424 1338 62% 708661 37% 784 614 56% 918 658 58% 1411 1265 56% 1274 1134 30% 1275 109357% 1403 1251 59% 1424 1098 60% 949 713 HTOJJ26 821702 2919 WUblastx.64(Q9UHT1) PRO1902 PROTEIN. Q9UHT1 71% 2969 2844 HTOJP25 853623 2920WUblastx.64 hypothetical L1 protein (third intron of pir|JU0033|JU003360% 1388 1519 gene TS) - human HTOJS23 737735 2921 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 57% 1564 1523 CLONE COL04765. 46% 1670 157559% 1833 1657 HTOJY56 664504 2922 WUblastx.64 (Q9P1F2) PRO2032. Q9P1F2100% 88 240 HTPCO75 853645 2925 WUblastx.64 (O00549) ORF2-LIKE PROTEINO00549 43% 325 26 (FRAGMENT). 36% 1318 1253 HTPDD68 590530 2927WUblastx.64 (Q9H0G2) HYPOTHETICAL 136.4 KDA Q9H0G2 88% 10 2004 PROTEIN.HTSET62 833692 2930 WUblastx.64 (Q9HCS4) HMG-BOX Q9HCS4 95% 59 124TRANSCRIPTION FACTOR TCF-3. 66% 124 327 HTSFV18 609939 2931 HMMER PFAM:Low-density lipoprotein PF00057 49.4 170 280 2.1.1 receptor domain classA WUblastx.64 LDL receptor related protein 105 - pir|T00204|T00204 82%10 984 human HTSGO13 789723 2932 WUblastx.64 (Q9NWJ5) CDNA FLJ20807 FIS,Q9NWJ5 99% 195 548 CLONE ADSE01784. 97% 489 845 HTSGO88 634834 2933WUblastx.64 (O60448) NEURONAL THREAD O60448 76% 797 612 PROTEINAD7C-NTP. 52% 640 521 66% 636 574 45% 560 492 69% 791 627 61% 137 75HTTAH05 772560 2934 WUblastx.64 (Q9H397) PRO2852. Q9H397 60% 548 676 39%684 926 HTTBJ38 863131 2936 WUblastx.64 (Q9VST7) CG4911 PROTEIN. Q9VST725% 497 1177 HTTDB11 638132 2937 WUblastx.64 (Q99LX8) UNKNOWN (PROTEINQ99LX8 100% 130 240 FOR MGC: 7346). HTTDG27 608318 2938 WUblastx.64(O62658) LINE-1 ELEMENT ORF2. O62658 44% 454 380 35% 392 3 HTTDN24766485 2939 WUblastx.64 (Q9BVN5) HYPOTHETICAL 120.6 KDA Q9BVN5 95% 6281725 PROTEIN. 32% 937 1593 95% 3 629 32% 1114 1596 HTTDO33 899418 2940WUblastx.64 (Q96GQ9) Unknown (protein for Q96GQ9 95% 22 753 MGC: 16648).HTTEO25 853403 2942 WUblastx.64 (Q9BWK9) UNKNOWN (PROTEIN Q9BWK9 97%1314 1424 FOR IMAGE: 2900813) (FRAGMENT). HTTEP11 562023 2943WUblastx.64 hypothetical protein pir|T46441|T46441 70% 753 830DKFZp434C0927.1 - human 74% 1006 1110 51% 812 928 100% 625 753 HTTES77844417 2944 WUblastx.64 (AAK40083) Inhibin binding protein AAK40083 82%697 2085 long isoform. 37% 3 725 31% 6 713 30% 93 704 36% 659 733 39%697 1818 34% 697 1815 33% 982 1818 88% 3 719 33% 697 1827 31% 1096 182131% 736 1833 35% 45 719 28% 901 1761 35% 6 737 34% 9 680 32% 45 716 36%1240 1818 HTTFG15 600377 2946 WUblastx.64 (Q9GMK2) HYPOTHETICAL 10.0 KDAQ9GMK2 66% 327 482 PROTEIN. HTWAM19 618318 2947 WUblastx.64 (Q9H728)CDNA: FLJ21463 FIS, Q9H728 76% 1852 1763 CLONE COL04765. 64% 1764 1525HTWBO30 655371 2949 WUblastx.64 (Q9N083) UNNAMED PORTEIN Q9N083 47% 560453 PRODUCT. 55% 751 578 HTWBZ57 828030 2950 WUblastx.64 (O95273) D-TYPECYCLIN- O95273 87% 218 1276 INTERACTING PROTEIN 1. HTWCC10 747687 2951WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 60% 1051 947 CLONEKAIA0536. 63% 1241 1095 HTWCE14 762839 2952 WUblastx.64 (Q9BSZ7) UNKNOWN(PROTEIN Q9BSZ7 100% 121 231 FOR MGC: 4322). HTWCT76 767758 2953WUblastx.64 (Q9BGW3) HYPOTHETICAL 13.5 KDA Q9BGW3 68% 1550 1368 PROTEIN.58% 1361 1311 HTWDJ17 784037 2954 WUblastx.64 (Q9CYV6) 2810439F02RIKQ9CYV6 93% 17 1255 PROTEIN. HTWDM89 569787 2955 WUblastx.64 (Q9P195)PRO1722. Q9P195 63% 1413 1267 61% 1277 1098 HTWEQ36 823369 2958WUblastx.64 (Q9NXK9) CDNA FLJ20187 FIS, Q9NXK9 68% 748 891 CLONECOLF0433. HTWFA88 596942 2960 WUblastx.64 probable transposase - humanpir|S72481|S72481 58% 1286 1357 transposon MER37 70% 1350 1559 51% 7091272 HTWFO43 858741 2962 WUblastx.64 (O60448) NEURONAL THREAD O60448 67%890 627 PROTEIN AD7C-NTP. 62% 1241 1056 63% 754 689 62% 1108 980 65%1242 1102 61% 905 744 53% 684 601 40% 790 665 58% 675 625 34% 1184 97535% 863 744 61% 1257 1039 45% 1063 992 64% 657 607 40% 1215 1087 34% 778659 100% 1016 996 HTXAD75 745410 2965 WUblastx.64 (Q9GLG1) CALPAIN 2.Q9GLG1 92% 345 917 HTXAR92 656935 2966 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 77% 1578 1297 CLONE COL04765. HTXBU88 604985 2968WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 75% 771 736 CLONEKAIA0536. 65% 739 680 60% 701 453 HTXCP27 892364 2969 WUblastx.64(AAH00057) Protein phosphatase 1G AAH00057 97% 521 628 (formerly 2C), ma100% 946 1149 98% 285 524 HTXCU30 839846 2970 WUblastx.64 (Q9H728) CDNA:FLJ21463 FIS, Q9H728 81% 706 641 CLONE COL04765. 80% 639 577 59% 875 684HTXCV44 740773 2971 WUblastx.64 (Q9HA67) CDNA FLJ12155 FIS, Q9HA67 52%883 945 CLONE MAMMA1000472. 70% 809 898 63% 630 803 63% 1521 1366 68%1370 1323 HTXDJ75 562780 2973 WUblastx.64 (Q26195) PVA1 GENE. Q26195 51%1598 1335 HTXDT72 778083 2977 WUblastx.64 (Q9BSV9) SIMILAR TO 95 KDAQ9BSV9 100% 8 400 RETINOBLASTOMA PROTEIN BINDING PROTEIN, KI HTXDZ68824545 2979 WUblastx.64 (Q9P0D0) HSPC106 (FRAGMENT). Q9P0D0 72% 80 27754% 136 498 HTXEN33 589556 2980 WUblastx.64 (Q99419) ICSAT TRANSCRIPTIONQ99419 78% 843 968 FACTOR (FRAGMENT). HTXJD08 566885 2985 WUblastx.64(Q14288) HYPOTHETICAL Q14288 59% 743 1111 PROTEIN (FRAGMENT). 47% 604756 45% 395 583 HTXJD85 840391 2986 WUblastx.64 (Q9HAD8) CDNA FLJ11786FIS, Q9HAD8 52% 1093 818 CLONE HEMBA1006036. HTXJI59 869905 2988WUblastx.64 (O15290) P66SHC. O15290 93% 1708 1571 HTXJJ92 688062 2989WUblastx.64 (Q9N044) UNNAMED PROTEIN Q9N044 59% 709 614 PRODUCT. 66% 611531 HTXJM94 853413 2990 WUblastx.64 (Q9Y2S9) HSPC019. Q9Y2S9 83% 44 262HTXJW06 789201 2992 WUblastx.64 (Q9UI28) ADRENAL GLAND Q9UI28 100% 868623 PROTEIN AD-003. HTXKB57 844329 2993 WUblastx.64 (Q9P073) HSPC309(FRAGMENT). Q9P073 94% 1072 1128 65% 1125 1523 HTXKH40 600378 2995WUblastx.64 (Q9Y380) CGI-71 PROTEIN. Q9Y380 94% 9 290 HTXKK76 8587552996 WUblastx.64 pro-pol-dUTPase polyprotein - murine pir|T29097|T2909744% 466 2 endogenous retrovirus ERV-L (fragment) HTXKL53 783141 2997WUblastx.64 (Q9Y3F0) CGI-05 PROTEIN. Q9Y3F0 100% 1315 1359 90% 3 89HTXLC05 843523 3000 WUblastx.64 (Q9H189) SPHINGOSINE-1- Q9H189 25% 4 531PHOSPHATASE. HTXLY94 844165 3003 WUblastx.64 hypothetical proteinpir|T14744|T14744 64% 77 643 DKFZp586F0424.1 - human (fragment) HTXNV66840597 3004 WUblastx.64 (Q9UJY4) ADP-RIBOSYLATION GGA2_HUMAN 99% 18 431FACTOR BINDING PROTEIN GGA2 (GOLG HTXOW27 839280 3006 WUblastx.64(Q9P2V7) PROTEIN CONTAINING Q9P2V7 100% 1652 2086 CXXC DOMAIN 1 92% 13091656 (HYPOTHETICAL 75.7 KDA PROT 78% 229 1188 HTXPD86 834772 3007WUblastx.64 (Q9UGP9) WD-REPEAT PROTEIN 5 WDR5_HUMAN 95% 74 1132(FRAGMENT). HTXPT57 897834 3008 WUblastx.64 (O60448) NEURONAL THREADO60448 60% 939 838 PROTEIN AD7C-NTP. 52% 693 544 42% 564 451 53% 471 42726% 722 543 35% 725 474 37% 1123 938 45% 974 849 53% 705 526 40% 1054911 53% 911 834 75% 1104 1069 64% 891 841 51% 551 432 57% 425 384 52%1084 926 HTYSJ88 598718 3009 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 64% 729 457 CLONE KAIA0536. HUFAB57 587275 3012 WUblastx.64ISOFORM B OF Q9UNP9 sp_vs|Q9UNP9- 94% 1266 1316 01|Q9UNP9 53% 826 1035HUFAO92 608175 3014 WUblastx.64 (Q9D922) 1810010G06RIK Q9D922 69% 232522 PROTEIN. HUFAO94 668267 3015 WUblastx.64 (Q9UI14) PRENYLATED RABQ9UI14 100% 3 551 ACCEPTOR 1. HUFAP33 600379 3016 HMMER PFAM: Zonapellucida-like domain PF00100 223.2 282 1016 2.1.1 WUblastx.64 (Q9Y211)DMBT1 PROTEIN. Q9Y211 93% 228 1016 100% 26 226 43% 29 217 41% 445 54638% 445 546 38% 445 522 100% 1013 1117 HUFBV62 742892 3020 WUblastx.64(Q9CWU4) 2410004B18RIK Q9CWU4 76% 76 264 PROTEIN. HUKAD46 604986 3024WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS, Q9NX85 46% 589 747 CLONEKAIA0536. 63% 377 598 HUKCS86 826468 3027 WUblastx.64 (Q9NX09) CDNAFLJ20500 FIS, Q9NX09 82% 201 896 CLONE KAT09159. HUKCS86 844245 3028WUblastx.64 (Q9NX09) CDNA FLJ20500 FIS, Q9NX09 82% 201 896 CLONEKAT09159. HUKEA22 702029 3029 WUblastx.64 (Q9PTD7) CINGULIN. Q9PTD7 68%575 12 HUKFC71 1300740 3032 WUblastx.64 (P82914) 28S RIBOSOMALRT15_HUMAN 97% 292 414 PROTEIN S15, MITOCHONDRIAL 65% 408 929 PRECURSORHUKFC71 845161 3111 blastx.2 MITOCHONDRIAL 28S sp|P82914|P82914 100% 293931 RIBOSOMAL PROTEIN S15 (MRP- S15). HUKFV37 844644 3033 WUblastx.64(AAH00407) Synaptogyrin 2. AAH00407 91% 49 720 HUNAL39 559448 3035WUblastx.64 (Q14288) HYPOTHETICAL Q14288 81% 1009 629 PROTEIN(FRAGMENT). HUSAO04 877889 3036 HMMER PFAM: tRNA synthetases class I (WPF00579 260.4 255 965 2.1.1 and Y) WUblastx.64 (Q9H817) CDNA FLJ13995FIS, Q9H817 92% 30 1451 CLONE Y79AA1002209, WEAKLY SIMILAR TO TYRHUSAO04 870791 3037 HMMER PFAM: tRNA synthetases class I (W PF00579212.2 297 965 2.1.1 and Y) WUblastx.64 (Q9H817) CDNA FLJ13995 FIS,Q9H817 92% 30 1451 CLONE Y79AA1002209, WEAKLY SIMILAR TO TYR HUSCA09853417 3038 HMMER PFAM: Leucine Rich Repeat PF00560 69.9 1259 1327 2.1.1WUblastx.64 (Q9H075) HYPOTHETICAL 81.8 KDA Q9H075 52% 44 1615 PROTEIN.HUSCJ01 740775 3039 WUblastx.64 (Q9CWP6) 2410013I23RIK Q9CWP6 70% 1 252PROTEIN. HUSGB23 704094 3040 WUblastx.64 (Q9H0F5) HYPOTHETICAL 43.9 KDAQ9H0F5 97% 143 247 PROTEIN. HUSGY15 759888 3043 WUblastx.64 (Q9JKN1)ZINC TRANSPORTER Q9JKN1 76% 162 1289 LIKE 2 (1810059J10RIK PROTEIN).HUSHD41 866498 3044 WUblastx.64 (BAB55441) CDNA FLJ14993 fis, BAB5544186% 2575 1541 clone Y79AA1001874, w 50% 2569 2483 HUSHK65 847188 3045HMMER PFAM: CUB domain PF00431 292.1 887 1222 2.1.1 WUblastx.64(AAG41897) Neuropilin-2a(17). AAG41897 97% 806 2122 95% 2727 3023 82%3046 3579 92% 2089 2721 32% 2086 2619 31% 1547 2086 92% 3008 3046HUSIK45 853932 3046 WUblastx.64 (Q96CN8) Hypothetical 30.9 kDa Q96CN891% 23 454 protein (Fragment). HUSIO57 886206 3047 WUblastx.64 (Q9Y3E2)HYPOTHETICAL YCE3_HUMAN 100% 170 565 PROTEIN CGI-143. HUSIR70 8381633049 WUblastx.64 (Q9HDC9) BSCV PROTEIN Q9HDC9 97% 1 345 (FRAGMENT).HUSXP50 561962 3050 WUblastx.64 (Q63777) HYPOTHETICAL 32.0 KDA Q6377726% 178 291 PROTEIN. 57% 27 68 55% 113 172 HUVCQ68 561963 3053WUblastx.64 (Q9BV40) SIMILAR TO VESICLE- Q9BV40 82% 40 339 ASSOCIATEDMEMBRANE PROTEIN 8 (ENDOBREVIN HUVEG53 797556 3055 WUblastx.64 (O62658)LINE-1 ELEMENT ORF2. O62658 35% 1843 1676 39% 2148 1939 60% 1391 1263HWAAH11 815548 3056 WUblastx.64 (Q9HAB3) CDNA FLJ11856 FIS, Q9HAB3 74%362 754 CLONE HEMBA1006789 (SIMILAR TO HYPOTHETIC HWAAQ28 806588 3057WUblastx.64 (Q9NZZ8) HSPC169 Q9NZZ8 96% 62 676 (HYPOTHETICAL 33.9 KDA23% 649 801 PROTEIN). 100% 651 980 HWAAY60 745917 3058 WUblastx.64(Q9BQA1) BA552M11.2.2 (NOVEL Q9BQA1 76% 504 722 PROTEIN (ISOFORM 2))(UNKNOWN) (PROTEIN HWABR43 823367 3059 WUblastx.64 (Q9BVD9) UNKNOWN(PROTEIN Q9BVD9 75% 2081 2034 FOR MGC: 5149). 79% 2266 2093 HWACZ33827311 3061 WUblastx.64 (Q9CTA6) 1110035E02RIK Q9CTA6 62% 389 436PROTEIN (FRAGMENT). 73% 234 392 HWADV90 897732 3062 WUblastx.64 (Q9NX17)CDNA FLJ20489 FIS, Q9NX17 78% 2375 2163 CLONE KAT08285. HWAEB52 8732073063 WUblastx.64 (Q9H8U5) CDNA FLJ13219 FIS, Q9H8U5 68% 878 1426 CLONENT2RP4001849, WEAKLY 60% 389 685 SIMILAR TO SH3 23% 356 667 28% 874 111331% 1191 1286 40% 344 442 35% 299 466 HWBAK71 853581 3064 WUblastx.64(Q9T9V8) NADH Q9T9V8 87% 77 175 DEHYDROGENASE SUBUNIT 3. 83% 305 340HWBBU75 780360 3065 WUblastx.64 (Q9R189) MUNC13-4 PROTEIN. Q9R189 82%1454 2362 73% 913 1434 80% 194 952 62% 2229 2729 31% 1586 1711 34% 401532 HWBCN81 853580 3066 WUblastx.64 (Q9H101) DJ776F14.2 (A NOVEL Q9H10194% 195 560 PROTEIN MEMBER OF THE PTPNS 33% 222 560 (PROTEIN TYR 100%150 221 HWBCX93 853418 3068 WUblastx.64 (Q9NX85) CDNA FLJ20378 FIS,Q9NX85 80% 642 553 CLONE KAIA0536. 84% 796 641 HWHGV77 788555 3072WUblastx.64 (Q9D6W1) 2310050C09RIK Q9D6W1 70% 136 621 PROTEIN. 51% 127552 37% 127 588 47% 124 318 100% 721 756 HWHGW09 702032 3073 HMMER PFAM:Uncharacterized protein family PF01027 68.3 271 444 2.1.1 WUblastx.64(Q9Y3C2) CGI-119 PROTEIN. Q9Y3C2 84% 256 450 HWHPU44 778090 3075WUblastx.64 (Q9H1C8) PUTATIVE Q9H1C8 97% 311 547 CYTOPLASMATIC PROTEIN.HWLAT50 840753 3077 WUblastx.64 (Q99JR4) UNKNOWN (PROTEIN Q99JR4 48%1864 2106 FOR IMAGE: 3599558) (FRAGMENT). HWLGP26 834770 3079WUblastx.64 (Q9NP87) DNA POLYMERASE MU. Q9NP87 93% 674 760 100% 269 29894% 295 465 87% 432 623 100% 3 254 HWLHO31 837480 3080 WUblastx.64(Q9NQT8) KINESIN-LIKE PROTEIN Q9NQT8 100% 41 205 GAKIN. 96% 190 1674HWLJN08 800626 3082 WUblastx.64 (Q9BX68) HIT-17 KDA. Q9BX68 99% 434 844HWLRE03 831198 3083 WUblastx.64 (O60646) HYPOTHETICAL 53.8 KDA O60646100% 1008 1232 PROTEIN (FRAGMENT). 99% 1238 2431 HWTBL86 791720 3089WUblastx.64 hypothetical protein pir|T17285|T17285 91% 1 1080DKFZp434N0535.1 - human (fragment) HWTBX66 732187 3090 WUblastx.64(Q9BRI8) UNKNOWN (PROTEIN Q9BRI8 71% 63 1073 FOR MGC: 11332). HYAAD61897736 3092 WUblastx.64 (O21101) ATPASE 6/8 O21101 56% 2009 2179(FRAGMENT). HYBAP75 853561 3094 WUblastx.64 (Q9N032) UNNAMED PROTEINQ9N032 64% 909 1025 PRODUCT.RACE Protocol for Recovery of Full-Length Genes

Partial cDNA clones can be made full-length by utilizing the rapidamplification of cDNA ends (RACE) procedure described in Frohman, M. A.,et al., Proc. Nat'l. Acad. Sci. USA, 85:8998-9002 (1988). A cDNA clonemissing either the 5′ or 3′ end can be reconstructed to include theabsent base pairs extending to the translational start or stop codon,respectively. In some cases, cDNAs are missing the start codon oftranslation, therefor. The following briefly describes a modification ofthis original 5′ RACE procedure. Poly A+ or total RNA is reversetranscribed with Superscript II (Gibco/BRL) and an antisense orcomplementary primer specific to the cDNA sequence. The primer isremoved from the reaction with a Microcon Concentrator (Amicon). Thefirst-strand cDNA is then tailed with dATP and terminal deoxynucleotidetransferase (Gibco/BRL). Thus, an anchor sequence is produced which isneeded for PCR amplification. The second strand is synthesized from thedA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), anoligo-dT primer containing three adjacent restriction sites (XhoI, SalIand ClaI) at the 5′ end and a primer containing just these restrictionsites. This double-stranded cDNA is PCR amplified for 40 cycles with thesame primers as well as a nested cDNA-specific antisense primer. The PCRproducts are size-separated on an ethidium bromide-agarose gel and theregion of gel containing cDNA products the predicted size of missingprotein-coding DNA is removed. cDNA is purified from the agarose withthe Magic PCR Prep kit (Promega), restriction digested with XhoI orSalI, and ligated to a plasmid such as pBluescript SKII (Stratagene) atXhoI and EcoRV sites. This DNA is transformed into bacteria and theplasmid clones sequenced to identify the correct protein-coding inserts.Correct 5′ ends are confirmed by comparing this sequence with theputatively identified homologue and overlap with the partial cDNA clone.Similar methods known in the art and/or commercial kits are used toamplify and recover 3′ ends.

Several quality-controlled kits are commercially available for purchase.Similar reagents and methods to those above are supplied in kit formfrom Gibco/BRL for both 5′ and 3′ RACE for recovery of full lengthgenes. A second kit is available from Clontech which is a modificationof a related technique, SLIC (single-stranded ligation tosingle-stranded cDNA), developed by Dumas et al., Nucleic Acids Res.,19:5227-32 (1991). The major differences in procedure are that the RNAis alkaline hydrolyzed after reverse transcription and RNA ligase isused to join a restriction site-containing anchor primer to thefirst-strand cDNA. This obviates the necessity for the dA-tailingreaction which results in a polyT stretch that is difficult to sequencepast.

An alternative to generating 5′ or 3′ cDNA from RNA is to use cDNAlibrary double-stranded DNA. An asymmetric PCR-amplified antisense cDNAstrand is synthesized with an antisense cDNA-specific primer and aplasmid-anchored primer. These primers are removed and a symmetric PCRreaction is performed with a nested cDNA-specific antisense primer andthe plasmid-anchored primer.

RNA Ligase Protocol for Generating the 5′ or 3′ End Sequences to ObtainFull Length Genes

Once a gene of interest is identified, several methods are available forthe identification of the 5′ or 3′ portions of the gene which may not bepresent in the original cDNA plasmid. These methods include, but are notlimited to, filter probing, clone enrichment using specific probes andprotocols similar and identical to 5′ and 3′ RACE. While the full lengthgene may be present in the library and can be identified by probing, auseful method for generating the 5′ or 3′ end is to use the existingsequence information from the original cDNA to generate the missinginformation. A method similar to 5′ RACE is available for generating themissing 5′ end of a desired full-length gene. (This method was publishedby Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684 (1993)).Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of apopulation of RNA presumably containing full-length gene RNA transcriptand a primer set containing a primer specific to the ligated RNAoligonucleotide and a primer specific to a known sequence of the gene ofinterest, is used to PCR amplify the 5′ portion of the desired fulllength gene which may then be sequenced and used to generate the fulllength gene. This method starts with total RNA isolated from the desiredsource, poly A RNA may be used but is not a prerequisite for thisprocedure. The RNA preparation may then be treated with phosphatase ifnecessary to eliminate 5′ phosphate groups on degraded or damaged RNAwhich may interfere with the later RNA ligase step. The phosphatase ifused is then inactivated and the RNA is treated with tobacco acidpyrophosphatase in order to remove the cap structure present at the 5′ends of messenger RNAs. This reaction leaves a 5′ phosphate group at the5′ end of the cap cleaved RNA which can then be ligated to an RNAoligonucleotide using T4 RNA ligase. This modified RNA preparation canthen be used as a template for first strand cDNA synthesis using a genespecific oligonucleotide. The first strand synthesis reaction can thenbe used as a template for PCR amplification of the desired 5′ end usinga primer specific to the ligated RNA oligonucleotide and a primerspecific to the known sequence of the gene of interest. The resultantproduct is then sequenced and analyzed to confirm that the 5′ endsequence belongs to the relevant gene.

The present invention also relates to vectors or plasmids which includesuch DNA sequences, as well as the use of the DNA sequences. Thematerial deposited with the ATCC (e.g., as described in columns 2 and 3of Table 1A, and/or as set forth in Table 1B, Table 6, or Table 7) is amixture of cDNA clones derived from a variety of human tissue and clonedin either a plasmid vector or a phage vector, as described, for example,in Table 1A and Table 7. These deposits are referred to as “thedeposits” herein. The tissues from which some of the clones were derivedare listed in Table 7, and the vector in which the corresponding cDNA iscontained is also indicated in Table 7. The deposited material includescDNA clones corresponding to SEQ ID NO:X described, for example, inTable 1A and/or 1B (ATCC Deposit No: Z). A clone which is isolatablefrom the ATCC Deposits by use of a sequence listed as SEQ ID NO:X, mayinclude the entire coding region of a human gene or in other cases suchclone may include a substantial portion of the coding region of a humangene. Furthermore, although the sequence listing may in some instanceslist only a portion of the DNA sequence in a clone included in the ATCCDeposits, it is well within the ability of one skilled in the art tosequence the DNA included in a clone contained in the ATCC Deposits byuse of a sequence (or portion thereof) described in, for example Tables1A and/or 1B or 2, by procedures hereinafter further described, andothers apparent to those skilled in the art.

Also provided in Table 1A and 7 is the name of the vector which containsthe cDNA clone. Each vector is routinely used in the art. The followingadditional information is provided for convenience.

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Phagemid pBS may be excised fromthe Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excisedfrom the Zap Express vector. Both phagemids may be transformed into E.coli strain XL-1 Blue, also available from Stratagene.

Vectors pSport1, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, wereobtained from Life Technologies, Inc., P.O. Box 6009, Gaithersburg, Md.20897. All Sport vectors contain an ampicillin resistance gene and maybe transformed into E. coli strain DH10B, also available from LifeTechnologies. See, for instance, Gruber, C. E., et al., Focus15:59-(1993). Vector lafinid BA (Bento Soares, Columbia University, NewYork, N.Y.) contains an ampicillin resistance gene and can betransformed into E. coli strain XL-1 Blue. Vector pCR®2.1, which isavailable from Invitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008,contains an ampicillin resistance gene and may be transformed into E.coli strain DH10B, available from Life Technologies. See, for instance,Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991).

The present invention also relates to the genes corresponding to SEQ IDNO:X, SEQ ID NO:Y, and/or the deposited clone (ATCC Deposit No: Z). Thecorresponding gene can be isolated in accordance with known methodsusing the sequence information disclosed herein. Such methods includepreparing probes or primers from the disclosed sequence and identifyingor amplifying the corresponding gene from appropriate sources of genomicmaterial.

Also provided in the present invention are allelic variants, orthologs,and/or species homologs. Procedures known in the art can be used toobtain full-length genes, allelic variants, splice variants, full-lengthcoding portions, orthologs, and/or species homologs of genescorresponding to SEQ ID NO:X or the complement thereof, polypeptidesencoded by genes corresponding to SEQ ID NO:X or the complement thereof,and/or the cDNA contained in ATCC Deposit No: Z, using information fromthe sequences disclosed herein or the clones deposited with the ATCC.For example, allelic variants and/or species homologs may be isolatedand identified by making suitable probes or primers from the sequencesprovided herein and screening a suitable nucleic acid source for allelicvariants and/or the desired homologue.

The polypeptides of the invention can be prepared in any suitablemanner. Such polypeptides include isolated naturally occurringpolypeptides, recombinantly produced polypeptides, syntheticallyproduced polypeptides, or polypeptides produced by a combination ofthese methods. Means for preparing such polypeptides are well understoodin the art.

The polypeptides may be in the form of the secreted protein, includingthe mature form, or may be a part of a larger protein, such as a fusionprotein (see below). It is often advantageous to include an additionalamino acid sequence which contains secretory or leader sequences,pro-sequences, sequences which aid in purification, such as multiplehistidine residues, or an additional sequence for stability duringrecombinant production.

The polypeptides of the present invention are preferably provided in anisolated form, and preferably are substantially purified. Arecombinantly produced version of a polypeptide, including the secretedpolypeptide, can be substantially purified using techniques describedherein or otherwise known in the art, such as, for example, by theone-step method described in Smith and Johnson, Gene 67:31-40 (1988).Polypeptides of the invention also can be purified from natural,synthetic or recombinant sources using techniques described herein orotherwise known in the art, such as, for example, antibodies of theinvention raised against the polypeptides of the present invention inmethods which are well known in the art.

The present invention provides a polynucleotide comprising, oralternatively consisting of, the nucleic acid sequence of SEQ ID NO:X,and/or the cDNA sequence contained in ATCC Deposit No: Z. The presentinvention also provides a polypeptide comprising, or alternatively,consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptideencoded by SEQ ID NO:X or a complement thereof, a polypeptide encoded bythe cDNA contained in ATCC Deposit No: Z, and/or the polypeptidesequence encoded by a nucleotide sequence in SEQ ID NO:B as defined incolumn 6 of Table 1C. Polynucleotides encoding a polypeptide comprising,or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y,a polypeptide encoded by SEQ ID NO:X, a polypeptide encoded by the cDNAcontained in ATCC Deposit No: Z, and/or a polypeptide sequence encodedby a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table1C are also encompassed by the invention. The present invention furtherencompasses a polynucleotide comprising, or alternatively consisting of,the complement of the nucleic acid sequence of SEQ ID NO:X, a nucleicacid sequence encoding a polypeptide encoded by the complement of thenucleic acid sequence of SEQ ID NO:X, and/or the cDNA contained in ATCCDeposit No: Z.

Moreover, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in Table 1Ccolumn 6, or any combination thereof. Additional, representativeexamples of polynucleotides of the invention comprise, or alternativelyconsist of, one, two, three, four, five, six, seven, eight, nine, ten,or more of the complementary strand(s) of the sequences delineated inTable 1C column 6, or any combination thereof. In further embodiments,the above-described polynucleotides of the invention comprise, oralternatively consist of, sequences delineated in Table 1C, column 6,and have a nucleic acid sequence which is different from that of the BACfragment having the sequence disclosed in SEQ ID NO:B (see Table 1C,column 5). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in Table 1C, column 6, and have a nucleic acidsequence which is different from that published for the BAC cloneidentified as BAC ID NO:A (see Table 1C, column 4). In additionalembodiments, the above-described polynucleotides of the inventioncomprise, or alternatively consist of, sequences delineated in Table 1C,column 6, and have a nucleic acid sequence which is different from thatcontained in the BAC clone identified as BAC ID NO:A (see Table 1C,column 4). Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides andpolypeptides are also encompassed by the invention.

Further, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C which correspond to the same Clone ID (see Table 1C, column1), or any combination thereof. Additional, representative examples ofpolynucleotides of the invention comprise, or alternatively consist of,one, two, three, four, five, six, seven, eight, nine, ten, or more ofthe complementary strand(s) of the sequences delineated in column 6 ofTable 1C which correspond to the same Clone ID (see Table 1C, column 1),or any combination thereof. In further embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame Clone ID (see Table 1C, column 1) and have a nucleic acid sequencewhich is different from that of the BAC fragment having the sequencedisclosed in SEQ ID NO:B (see Table 1C, column 5). In additionalembodiments, the above-described polynucleotides of the inventioncomprise, or alternatively consist of, sequences delineated in column 6of Table 1C which correspond to the same Clone ID (see Table 1C,column 1) and have a nucleic acid sequence which is different from thatpublished for the BAC clone identified as BAC ID NO:A (see Table 1C,column 4). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame Clone ID (see Table 1C, column 1) and have a nucleic acid sequencewhich is different from that contained in the BAC clone identified asBAC ID NO:A (see Table 1C, column 4). Polypeptides encoded by thesepolynucleotides, other polynucleotides that encode these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention. Additionally, fragments and variants of the above-describedpolynucleotides and polypeptides are also encompassed by the invention.

Further, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C which correspond to the same contig sequence identifier SEQID NO:X (see Table 1C, column 2), or any combination thereof.Additional, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the complementary strand(s) of thesequences delineated in column 6 of Table 1C which correspond to thesame contig sequence identifier SEQ ID NO:X (see Table 1C, column 2), orany combination thereof. In further embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) andhave a nucleic acid sequence which is different from that of the BACfragment having the sequence disclosed in SEQ ID NO:B (see Table 1C,column 5). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in column 6 of Table 1C which correspond to thesame contig sequence identifier SEQ ID NO:X (see Table 1C, column 2) andhave a nucleic acid sequence which is different from that published forthe BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Inadditional embodiments, the above-described polynucleotides of theinvention comprise, or alternatively consist of, sequences delineated incolumn 6 of Table 1C which correspond to the same contig sequenceidentifier SEQ ID NO:X (see Table 1C, column 2) and have a nucleic acidsequence which is different from that contained in the BAC cloneidentified as BAC ID NO:A (See Table 1C, column 4). Polypeptides encodedby these polynucleotides, other polynucleotides that encode thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides and polypeptides are alsoencompassed by the invention.

Moreover, representative examples of polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in the samerow of Table 1C column 6, or any combination thereof. Additional,representative examples of polynucleotides of the invention comprise, oralternatively consist of, one, two, three, four, five, six, seven,eight, nine, ten, or more of the complementary strand(s) of thesequences delineated in the same row of Table 1C column 6, or anycombination thereof. In preferred embodiments, the polynucleotides ofthe invention comprise, or alternatively consist of, one, two, three,four, five, six, seven, eight, nine, ten, or more of the complementarystrand(s) of the sequences delineated in the same row of Table 1C column6, wherein sequentially delineated sequences in the table (i.e.corresponding to those exons located closest to each other) are directlycontiguous in a 5′ to 3′ orientation. In further embodiments,above-described polynucleotides of the invention comprise, oralternatively consist of, sequences delineated in the same row of Table1C, column 6, and have a nucleic acid sequence which is different fromthat of the BAC fragment having the sequence disclosed in SEQ ID NO:B(see Table 1C, column 5). In additional embodiments, the above-describedpolynucleotides of the invention comprise, or alternatively consist of,sequences delineated in the same row of Table 1C, column 6, and have anucleic acid sequence which is different from that published for the BACclone identified as BAC ID NO:A (see Table 1C, column 4). In additionalembodiments, the above-described polynucleotides of the inventioncomprise, or alternatively consist of, sequences delineated in the samerow of Table 1C, column 6, and have a nucleic acid sequence which isdifferent from that contained in the BAC clone identified as BAC ID NO:A(see Table 1C, column 4). Polypeptides encoded by these polynucleotides,other polynucleotides that encode these polypeptides, and antibodiesthat bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C, and the polynucleotide sequence of SEQ ID NO:X (e.g., asdefined in Table 1C, column 2) or fragments or variants thereof.Polypeptides encoded by these polynucleotides, other polynucleotidesthat encode these polypeptides, and antibodies that bind thesepolypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in column 6of Table 1C which correspond to the same Clone ID (see Table 1C, column1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined inTable 1A, 1B, or 1C) or fragments or variants thereof. In preferredembodiments, the delineated sequence(s) and polynucleotide sequence ofSEQ ID NO:X correspond to the same Clone ID. Polypeptides encoded bythese polynucleotides, other polynucleotides that encode thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more of the sequences delineated in the samerow of column 6 of Table 1C, and the polynucleotide sequence of SEQ IDNO:X (e.g., as defined in Table 1A, 1B, or 1C) or fragments or variantsthereof. In preferred embodiments, the delineated sequence(s) andpolynucleotide sequence of SEQ ID NO:X correspond to the same row ofcolumn 6 of Table 1C. Polypeptides encoded by these polynucleotides,other polynucleotides that encode these polypeptides, and antibodiesthat bind these polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of one of the sequences delineated in column 6of Table 1C and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:Xare directly contiguous. Nucleic acids which hybridize to the complementof these 20 contiguous polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions, are alsoencompassed by the invention. Polypeptides encoded by thesepolynucleotides and/or nucleic acids, other polynucleotides and/ornucleic acids that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides, nucleicacids, and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, a polynucleotide sequence inwhich the 3′ 10 polynucleotides of one of the sequences delineated incolumn 6 of Table 1C and the 5′ 10 polynucleotides of a fragment orvariant of the sequence of SEQ ID NO:X are directly contiguous Nucleicacids which hybridize to the complement of these 20 contiguouspolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of the sequence of SEQ ID NO:X and the 5′ 10polynucleotides of the sequence of one of the sequences delineated incolumn 6 of Table 1C are directly contiguous. Nucleic acids whichhybridize to the complement of these 20 contiguous polynucleotides understringent hybridization conditions or alternatively, under lowerstringency conditions, are also encompassed by the invention.Polypeptides encoded by these polynucleotides and/or nucleic acids,other polynucleotides and/or nucleic acids encoding these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention. Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of a fragment or variant of the sequence of SEQ ID NO:Xand the 5′ 10 polynucleotides of the sequence of one of the sequencesdelineated in column 6 of Table 1C are directly contiguous. Nucleicacids which hybridize to the complement of these 20 contiguouspolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides,are also encompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, a polynucleotide sequence inwhich the 3′ 10 polynucleotides of one of the sequences delineated incolumn 6 of Table 1C and the 5′ 10 polynucleotides of another sequencein column 6 are directly contiguous. Nucleic acids which hybridize tothe complement of these 20 contiguous polynucleotides under stringenthybridization conditions or alternatively, under lower stringencyconditions, are also encompassed by the invention. Polypeptides encodedby these polynucleotides and/or nucleic acids, other polynucleotidesand/or nucleic acids encoding these polypeptides, and antibodies thatbind these polypeptides are also encompassed by the invention.Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of one of the sequences delineated in column 6 of Table1C and the 5′ 10 polynucleotides of another sequence in column 6corresponding to the same Clone ID (see Table 1C, column 1) are directlycontiguous. Nucleic acids which hybridize to the complement of these 20lower stringency conditions, are also encompassed by the invention.Polypeptides encoded by these polynucleotides and/or nucleic acids,other polynucleotides and/or nucleic acids encoding these polypeptides,and antibodies that bind these polypeptides are also encompassed by theinvention. Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of, a polynucleotide sequence in which the 3′ 10polynucleotides of one sequence in column 6 corresponding to the samecontig sequence identifier SEQ ID NO:X (see Table 1C, column 2) aredirectly contiguous. Nucleic acids which hybridize to the complement ofthese 20 contiguous polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions, are alsoencompassed by the invention. Polypeptides encoded by thesepolynucleotides and/or nucleic acids, other polynucleotides and/ornucleic acids encoding these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides, nucleicacids, and polypeptides are also encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of a polynucleotide sequence in which the 3′ 10polynucleotides of one of the sequences delineated in column 6 of Table1C and the 5′ 10 polynucleotides of another sequence in column 6corresponding to the same row are directly contiguous. In preferredembodiments, the 3′ 10 polynucleotides of one of the sequencesdelineated in column 6 of Table 1C is directly contiguous with the 5′ 10polynucleotides of the next sequential exon delineated in Table 1C,column 6. Nucleic acids which hybridize to the complement of these 20contiguous polynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

Table 3

Many polynucleotide sequences, such as EST sequences, are publiclyavailable and accessible through sequence databases and may have beenpublicly available prior to conception of the present invention.Preferably, such related polynucleotides are specifically excluded fromthe scope of the present invention. Accordingly, for each contigsequence (SEQ ID NO:X) listed in the fifth column of Table 1A and/or thefourth column of Table 1B.1, preferably excluded are one or morepolynucleotides comprising a nucleotide sequence described by thegeneral formula of a-b, where a is any integer between 1 and the finalnucleotide minus 15 of SEQ ID NO:X, b is an integer of 15 to the finalnucleotide of SEQ ID NO:X, where both a and b correspond to thepositions of nucleotide residues shown in SEQ ID NO:X, and where b isgreater than or equal to a +14. More specifically, preferably excludedare one or more polynucleotides comprising a nucleotide sequencedescribed by the general formula of a-b, where a and b are integers asdefined in columns 4 and 5, respectively, of Table 3. In specificembodiments, the polynucleotides of the invention do not consist of atleast one, two, three, four, five, ten, or more of the specificpolynucleotide sequences referenced by the Genbank Accession No. asdisclosed in column 6 of Table 3 (including for example, publishedsequence in connection with a particular BAC clone). In furtherembodiments, preferably excluded from the invention are the specificpolynucleotide sequence(s) contained in the clones corresponding to atleast one, two, three, four, five, ten, or more of the availablematerial having the accession numbers identified in the sixth column ofthis Table (including for example, the actual sequence contained in anidentified BAC clone). In no way is this listing meant to encompass allof the sequences which may be excluded by the general formula, it isjust a representative example. All references available through theseaccessions are hereby incorporated by reference in their entirety.LENGTHY TABLE REFERENCED HERE US20070048297A1-20070301-T00006 Pleaserefer to the end of the specification for access instructions.Description of Table 4

Table 4 provides a key to the tissue/cell source identifier codedisclosed in Table 1B.2, column 5. Column 1 of Table 4 provides thetissue/cell source identifier code disclosed in Table 1B.2, Column 5.Columns 2-5 provide a description of the tissue or cell source. Notethat “Description” and “Tissue” sources (i.e. columns 2 and 3) havingthe prefix “a_” indicates organs, tissues, or cells derived from “adult”sources. Codes corresponding to diseased tissues are indicated in column6 with the word “disease.” The use of the word “disease” in column 6 isnon-limiting. The tissue or cell source may be specific (e.g. aneoplasm), or may be disease-associated (e.g., a tissue sample from anormal portion of a diseased organ). Furthermore, tissues and/or cellslacking the “disease” designation may still be derived from sourcesdirectly or indirectly involved in a disease state or disorder, andtherefore may have a further utility in that disease state or disorder.In numerous cases where the tissue/cell source is a library, column 7identifies the vector used to generate the library. TABLE 4 CodeDescription Tissue Organ Cell Line Disease Vector AR022 a_Heart a_HeartAR023 a_Liver a_Liver AR024 a_mammary gland a_mammary gland AR025a_Prostate a_Prostate AR026 a_small intestine a_small intestine AR027a_Stomach a_Stomach AR028 Blood B cells Blood B cells AR029 Blood Bcells activated Blood B cells activated AR030 Blood B cells restingBlood B cells resting AR031 Blood T cells activated Blood T cellsactivated AR032 Blood T cells resting Blood T cells resting AR033 brainbrain AR034 breast breast AR035 breast cancer breast cancer AR036 CellLine CAOV3 Cell Line CAOV3 AR037 cell line PA-1 cell line PA-1 AR038cell line transformed cell line transformed AR039 colon colon AR040colon (9808co65R) colon (9808co65R) AR041 colon (9809co15) colon(9809co15) AR042 colon cancer colon cancer AR043 colon cancer(9808co64R) colon cancer (9808co64R) AR044 colon cancer 9809co14 coloncancer 9809co14 AR050 Donor II B Cells 24 hrs Donor II B Cells 24 hrsAR051 Donor II B Cells 72 hrs Donor II B Cells 72 hrs AR052 Donor IIB-Cells 24 hrs. Donor II B-Cells 24 hrs. AR053 Donor II B-Cells 72 hrsDonor II B-Cells 72 hrs AR054 Donor II Resting B Cells Donor II RestingB Cells AR055 Heart Heart AR056 Human Lung (clonetech) Human Lung(clonetech) AR057 Human Mammary (clontech) Human Mammary (clontech)AR058 Human Thymus (clonetech) Human Thymus (clonetech) AR059 Jurkat(unstimulated) Jurkat (unstimulated) AR060 Kidney Kidney AR061 LiverLiver AR062 Liver (Clontech) Liver (Clontech) AR063 Lymphocytes chroniclymphocytic leukaemia Lymphocytes chronic lymphocytic leukaemia AR064Lymphocytes diffuse large B cell lymphoma Lymphocytes diffuse large Bcell lymphoma AR065 Lymphocytes follicular lymphoma Lymphocytesfollicular lymphoma AR066 normal breast normal breast AR067 NormalOvarian (4004901) Normal Ovarian (4004901) AR068 Normal Ovary 9508G045Normal Ovary 9508G045 AR069 Normal Ovary 9701G208 Normal Ovary 9701G208AR070 Normal Ovary 9806G005 Normal Ovary 9806G005 AR071 Ovarian CancerOvarian Cancer AR072 Ovarian Cancer (9702G001) Ovarian Cancer (9702G001)AR073 Ovarian Cancer (9707G029) Ovarian Cancer (9707G029) AR074 OvarianCancer (9804G011) Ovarian Cancer (9804G011) AR075 Ovarian Cancer(9806G019) Ovarian Cancer (9806G019) AR076 Ovarian Cancer (9807G017)Ovarian Cancer (9807G017) AR077 Ovarian Cancer (9809G001) Ovarian Cancer(9809G001) AR078 ovarian cancer 15799 ovarian cancer 15799 AR079 OvarianCancer 17717AID Ovarian Cancer 17717AID AR080 Ovarian Cancer 4004664B1Ovarian Cancer 4004664B1 AR081 Ovarian Cancer 4005315A1 Ovarian Cancer4005315A1 AR082 ovarian cancer 94127303 ovarian cancer 94127303 AR083Ovarian Cancer 96069304 Ovarian Cancer 96069304 AR084 Ovarian Cancer9707G029 Ovarian Cancer 9707G029 AR085 Ovarian Cancer 9807G045 OvarianCancer 9807G045 AR086 ovarian cancer 9809G001 ovarian cancer 9809G001AR087 Ovarian Cancer 9905C032RC Ovarian Cancer 9905C032RC AR088 Ovariancancer 9907 C00 3rd Ovarian cancer 9907 C00 3rd AR089 Prostate ProstateAR090 Prostate (clonetech) Prostate (clonetech) AR091 prostate cancerprostate cancer AR092 prostate cancer #15176 prostate cancer #15176AR093 prostate cancer #15509 prostate cancer #15509 AR094 prostatecancer #15673 prostate cancer #15673 AR095 Small Intestine (Clontech)Small Intestine (Clontech) AR096 Spleen Spleen AR097 Thymus T cellsactivated Thymus T cells activated AR098 Thymus T cells resting Thymus Tcells resting AR099 Tonsil Tonsil AR100 Tonsil geminal centercentroblast Tonsil geminal center centroblast AR101 Tonsil germinalcenter B cell Tonsil germinal center B cell AR102 Tonsil lymph nodeTonsil lymph node AR103 Tonsil memory B cell Tonsil memory B cell AR104Whole Brain Whole Brain AR105 Xenograft ES-2 Xenograft ES-2 AR106Xenograft SW626 Xenograft SW626 AR119 001: IL-2 001: IL-2 AR120 001:IL-2.1 001: IL-2.1 AR121 001: IL-2_b 001: IL-2_b AR124 002: Monocytesuntreated (1 hr) 002: Monocytes untreated (1 hr) AR125 002: Monocytesuntreated (5 hrs) 002: Monocytes untreated (5 hrs) AR126 002: Control.1C002: Control.1C AR127 002: IL2.1C 002: IL2.1C AR130 003: Placebo-treatedRat Lacrimal Gland 003: Placebo-treated Rat Lacrimal Gland AR131 003:Placebo-treated Rat Submandibular 003: Placebo-treated Rat GlandSubmandibular Gland AR135 004: Monocytes untreated (5 hrs) 004:Monocytes untreated (5 hrs) AR136 004: Monocytes untreated 1 hr 004:Monocytes untreated 1 hr AR139 005: Placebo (48 hrs) 005: Placebo (48hrs) AR140 006: pC4 (24 hrs) 006: pC4 (24 hrs) AR141 006: pC4 (48 hrs)006: pC4 (48 hrs) AR152 007: PHA(1 hr) 007: PHA(1 hr) AR153 007: PHA(6HRS) 007: PHA(6 HRS) AR154 007: PMA(6 hrs) 007: PMA(6 hrs) AR155 008:1449_#2 008: 1449_#2 AR161 01: A - max 24 01: A - max 24 AR162 01: A -max 26 01: A - max 26 AR163 01: A - max 30 01: A - max 30 AR164 01: B -max 24 01: B - max 24 AR165 01: B - max 26 01: B - max 26 AR166 01: B -max 30 01: B - max 30 AR167 1449 Sample 1449 Sample AR168 3T3P10 1.0 uMinsulin 3T3P10 1.0 uM insulin AR169 3T3P10 10 nM Insulin 3T3P10 10 nMInsulin AR170 3T3P10 10 uM insulin 3T3P10 10 uM insulin AR171 3T3P10 NoInsulin 3T3P10 No Insulin AR172 3T3P4 3T3P4 AR173 Adipose (41892)Adipose (41892) AR174 Adipose Diabetic (41611) Adipose Diabetic (41611)AR175 Adipose Diabetic (41661) Adipose Diabetic (41661) AR176 AdiposeDiabetic (41689) Adipose Diabetic (41689) AR177 Adipose Diabetic (41706)Adipose Diabetic (41706) AR178 Adipose Diabetic (42352) Adipose Diabetic(42352) AR179 Adipose Diabetic (42366) Adipose Diabetic (42366) AR180Adipose Diabetic (42452) Adipose Diabetic (42452) AR181 Adipose Diabetic(42491) Adipose Diabetic (42491) AR182 Adipose Normal (41843) AdiposeNormal (41843) AR183 Adipose Normal (41893) Adipose Normal (41893) AR184Adipose Normal (42452) Adipose Normal (42452) AR185 Adrenal GlandAdrenal Gland AR186 Adrenal Gland + Whole Brain Adrenal Gland + WholeBrain AR187 B7(1 hr) + (inverted) B7(1 hr) + (inverted) AR188 Breast(18275A2B) Breast (18275A2B) AR189 Breast (4004199) Breast (4004199)AR190 Breast (4004399) Breast (4004399) AR191 Breast (4004943B7) Breast(4004943B7) AR192 Breast (4005570B1) Breast (4005570B1) AR193 BreastCancer (4004127A30) Breast Cancer (4004127A30) AR194 Breast Cancer(400443A21) Breast Cancer (400443A21) AR195 Breast Cancer (4004643A2)Breast Cancer (4004643A2) AR196 Breast Cancer (4004710A7) Breast Cancer(4004710A7) AR197 Breast Cancer (4004943A21) Breast Cancer (4004943A21)AR198 Breast Cancer (400553A2) Breast Cancer (400553A2) AR199 BreastCancer (9805C046R) Breast Cancer (9805C046R) AR200 Breast Cancer(9806C012R) Breast Cancer (9806C012R) AR201 Breast Cancer (ODQ 45913)Breast Cancer (ODQ 45913) AR202 Breast Cancer (ODQ45913) Breast Cancer(ODQ45913) AR203 Breast Cancer (ODQ4591B) Breast Cancer (ODQ4591B) AR204Colon Cancer (15663) Colon Cancer (15663) AR205 Colon Cancer (4005144A4)Colon Cancer (4005144A4) AR206 Colon Cancer (4005413A4) Colon Cancer(4005413A4) AR207 Colon Cancer (4005570B1) Colon Cancer (4005570B1)AR208 Control RNA #1 Control RNA #1 AR209 Control RNA #2 Control RNA #2AR210 Cultured Preadipocyte (blue) Cultured Preadipocyte (blue) AR211Cultured Preadipocyte (Red) Cultured Preadipocyte (Red) AR212 Donor IIB-Cells 24 hrs Donor II B-Cells 24 hrs AR213 Donor II Resting B-CellsDonor II Resting B-Cells AR214 H114EP12 10 nM Insulin H114EP12 10 nMInsulin AR215 H114EP12 (10 nM insulin) H114EP12 (10 nM insulin) AR216H114EP12 (2.6 ug/ul) H114EP12 (2.6 ug/ul) AR217 H114EP12 (3.6 ug/ul)H114EP12 (3.6 ug/ul) AR218 HUVEC #1 HUVEC #1 AR219 HUVEC #2 HUVEC #2AR221 L6 undiff. L6 undiff. AR222 L6 Undifferentiated L6Undifferentiated AR223 L6P8 + 10 nM Insulin L6P8 + 10 nM Insulin AR224L6P8 + HS L6P8 + HS AR225 L6P8 10 nM Insulin L6P8 10 nM Insulin AR226Liver (00-06-A007B) Liver (00-06-A007B) AR227 Liver (96-02-A075) Liver(96-02-A075) AR228 Liver (96-03-A144) Liver (96-03-A144) AR229 Liver(96-04-A138) Liver (96-04-A138) AR230 Liver (97-10-A074B) Liver(97-10-A074B) AR231 Liver (98-09-A242A) Liver (98-09-A242A) AR232 LiverDiabetic (1042) Liver Diabetic (1042) AR233 Liver Diabetic (41616) LiverDiabetic (41616) AR234 Liver Diabetic (41955) Liver Diabetic (41955)AR235 Liver Diabetic (42352R) Liver Diabetic (42352R) AR236 LiverDiabetic (42366) Liver Diabetic (42366) AR237 Liver Diabetic (42483)Liver Diabetic (42483) AR238 Liver Diabetic (42491) Liver Diabetic(42491) AR239 Liver Diabetic (99-09-A281A) Liver Diabetic (99-09- A281A)AR240 Lung Lung AR241 Lung (27270) Lung (27270) AR242 Lung (2727Q) Lung(2727Q) AR243 Lung Cancer (4005116A1) Lung Cancer (4005116A1) AR244 LungCancer (4005121A5) Lung Cancer (4005121A5) AR245 Lung Cancer(4005121A5)) Lung Cancer (4005121A5)) AR246 Lung Cancer (4005340A4) LungCancer (4005340A4) AR247 Mammary Gland Mammary Gland AR248 Monocyte (CT)Monocyte (CT) AR249 Monocyte (OCT) Monocyte (OCT) AR250 Monocytes (CT)Monocytes (CT) AR251 Monocytes (INFG 18 hr) Monocytes (INFG 18 hr) AR252Monocytes (INFG 18 hr) Monocytes (INFG 18 hr) AR253 Monocytes (INFG8-11) Monocytes (INFG 8-11) AR254 Monocytes (OCT) Monocytes (OCT) AR255Muscle (91-01-A105) Muscle (91-01-A105) AR256 Muscle (92-04-A059) Muscle(92-04-A059) AR257 Muscle (97-11-A056d) Muscle (97-11-A056d) AR258Muscle (99-06-A210A) Muscle (99-06-A210A) AR259 Muscle (99-07-A203B)Muscle (99-07-A203B) AR260 Muscle (99-7-A203B) Muscle (99-7-A203B) AR261Muscle Diabetic (42352R) Muscle Diabetic (42352R) AR262 Muscle Diabetic(42366) Muscle Diabetic (42366) AR263 NK-19 Control NK-19 Control AR264NK-19 IL Treated 72 hrs NK-19 IL Treated 72 hrs AR265 NK-19 UK Treated72 hrs. NK-19 UK Treated 72 hrs. AR266 Omentum Normal (94-08-B009)Omentum Normal (94-08- B009) AR267 Omentum Normal (97-01-A039A) OmentumNormal (97-01- A039A) AR268 Omentum Normal (97-04-A114C) Omentum Normal(97-04- A114C) AR269 Omentum Normal (97-06-A117C) Omentum Normal (97-06-A117C) AR270 Omentum Normal (97-09-B004C) Omentum Normal (97-09- B004C)AR271 Ovarian Cancer (17717AID) Ovarian Cancer (17717AID) AR272 OvarianCancer (9905C023RC) Ovarian Cancer (9905C023RC) AR273 Ovarian Cancer(9905C032RC) Ovarian Cancer (9905C032RC) AR274 Ovary (9508G045) Ovary(9508G045) AR275 Ovary (9701G208) Ovary (9701G208) AR276 Ovary 9806G005Ovary 9806G005 AR277 Pancreas Pancreas AR278 Placebo Placebo AR279 rIL2Control rIL2 Control AR280 RSS288L RSS288L AR281 RSS288LC RSS288LC AR282Salivary Gland Salivary Gland AR283 Skeletal Muscle Skeletal MuscleAR284 Skeletal Muscle (91-01-A105) Skeletal Muscle (91-01- A105) AR285Skeletal Muscle (42180) Skeletal Muscle (42180) AR286 Skeletal Muscle(42386) Skeletal Muscle (42386) AR287 Skeletal Muscle (42461) SkeletalMuscle (42461) AR288 Skeletal Muscle (91-01-A105) Skeletal Muscle(91-01- A105) AR289 Skeletal Muscle (92-04-A059) Skeletal Muscle (92-04-A059) AR290 Skeletal Muscle (96-08-A171) Skeletal Muscle (96-08- A171)AR291 Skeletal Muscle (97-07-A190A) Skeletal Muscle (97-07- A190A) AR292Skeletal Muscle Diabetic (42352) Skeletal Muscle Diabetic (42352) AR293Skeletal Muscle Diabetic (42366) Skeletal Muscle Diabetic (42366) AR294Skeletal Muscle Diabetic (42395) Skeletal Muscle Diabetic (42395) AR295Skeletal Muscle Diabetic (42483) Skeletal Muscle Diabetic (42483) AR296Skeletal Muscle Diabetic (42491) Skeletal Muscle Diabetic (42491) AR297Skeletal Muscle Diabetic 42352 Skeletal Muscle Diabetic 42352 AR298Skeletal Musle (42461) Skeletal Musle (42461) AR299 Small IntestineSmall Intestine AR300 Stomach Stomach AR301 T-Cell + HDPBQ71.fc 1449 16hrs T-Cell + HDPBQ71.fc 1449 16 hrs AR302 T-Cell + HDPBQ71.fc 1449 6 hrsT-Cell + HDPBQ71.fc 1449 6 hrs AR303 T-Cell + IL2 16 hrs T-Cell + IL2 16hrs AR304 T-Cell + IL2 6 hrs T-Cell + IL2 6 hrs AR306 T-Cell Untreated16 hrs T-Cell Untreated 16 hrs AR307 T-Cell Untreated 6 hrs T-CellUntreated 6 hrs AR308 T-Cells 24 hours T-Cells 24 hours AR309 T-Cells 24hrs T-Cells 24 hrs AR310 T-Cells 24 hrs. T-Cells 24 hrs. AR311 T-Cells24 hrs T-Cells 24 hrs AR312 T-Cells 4 days T-Cells 4 days AR313 ThymusThymus AR314 TRE TRE AR315 TREC TREC AR316 Virtual Mixture VirtualMixture AR317 B lymphocyte, B lymphocyte, AR318 (non-T; non-B) (non-T;non-B) AR326 001-293 RNA (Vector Control) 001-293 RNA (Vector Control)AR327 001: Control 001: Control AR328 001: Control.1 001: Control.1AR355 Acute Lymphocyte Leukemia Acute Lymphocyte Leukemia AR356 AMLPatient #11 AML Patient #11 AR357 AML Patient #2 AML Patient #2 AR358AML Patient #2 SGAH AML Patient #2 SGAH AR359 AML Patient#2 AMLPatient#2 AR360 Aorta Aorta AR361 B Cell B Cell AR362 B lymphoblast Blymphoblast AR363 B lymphocyte B lymphocyte AR364 B lymphocytes Blymphocytes AR365 B-cell B-cell AR366 B-Cells B-Cells AR367B-Lymphoblast B-Lymphoblast AR368 B-Lymphocytes B-Lymphocytes AR369Bladder Bladder AR370 Bone Marrow Bone Marrow AR371 Bronchial EpithelialCell Bronchial Epithelial Cell AR372 Bronchial Epithelial CellsBronchial Epithelial Cells AR373 Caco-2A Caco-2A AR374 Caco-2B Caco-2BAR375 Caco-2C Caco-2C AR376 Cardiac #1 Cardiac #1 AR377 Cardiac #2Cardiac #2 AR378 Chest Muscle Chest Muscle AR381 Dendritic CellDendritic Cell AR382 Dendritic cells Dendritic cells AR383 E. coli E.coli AR384 Epithelial Cells Epithelial Cells AR385 Esophagus EsophagusAR386 FPPS FPPS AR387 FPPSC FPPSC AR388 HepG2 Cell Line HepG2 Cell LineAR389 HepG2 Cell line Buffer 1 hr. HepG2 Cell line Buffer 1 hr. AR390HepG2 Cell line Buffer 06 hr HepG2 Cell line Buffer 06 hr AR391 HepG2Cell line Buffer 24 hr. HepG2 Cell line Buffer 24 hr. AR392 HepG2 Cellline Insulin 01 hr. HepG2 Cell line Insulin 01 hr. AR393 HepG2 Cell lineInsulin 06 hr. HepG2 Cell line Insulin 06 hr. AR394 HepG2 Cell lineInsulin 24 hr. HepG2 Cell line insulin 24 hr. AR398 HMC-1 HMC-1 AR399HMCS HMCS AR400 HMSC HMSC AR401 HUVEC #3 HUVEC #3 AR402 HUVEC #4 HUVEC#4 AR404 KIDNEY NORMAL KIDNEY NORMAL AR405 KIDNEY TUMOR KIDNEY TUMORAR406 KIDNEY TUMOR AR407 Lymph Node Lymph Node AR408 MacrophageMacrophage AR409 Megakarioblast Megakarioblast AR410 Monocyte MonocyteAR411 Monocytes Monocytes AR412 Myocardium Myocardium AR413 Myocardium#3 Myocardium #3 AR414 Myocardium #4 Myocardium #4 AR415 Myocardium #5Myocardium #5 AR416 NK NK AR417 NK cell NK cell AR418 NK cells NK cellsAR419 NKYa NKYa AR420 NKYa019 NKYa019 AR421 Ovary Ovary AR422 Patient#11 Patient #11 AR423 Peripheral blood Peripheral blood AR424 PrimaryAdipocytes Primary Adipocytes AR425 Promyeloblast Promyeloblast AR427RSSWT RSSWT AR428 RSSWTC RSSWTC AR429 SW 480(G1) SW 480(G1) AR430 SW480(G2) SW 480(G2) AR431 SW 480(G3) SW 480(G3) AR432 SW 480(G4) SW480(G4) AR433 SW 480(G5) SW 480(G5) AR434 T Lymphoblast T LymphoblastAR435 T Lymphocyte T Lymphocyte AR436 T-Cell T-Cell AR438 T-Cell,T-Cell, AR439 T-Cells T-Cells AR440 T-lymphoblast T-lymphoblast AR441 Th1 Th 1 AR442 Th 2 Th 2 AR443 Th1 Th1 AR444 Th2 Th2 H0002 Human AdultHeart Human Adult Heart Heart Uni-ZAP XR H0003 Human Adult Liver HumanAdult Liver Liver Uni-ZAP XR H0004 Human Adult Spleen Human Adult SpleenSpleen Uni-ZAP XR H0007 Human Cerebellum Human Cerebellum Brain Uni-ZAPXR H0008 Whole 6 Week Old Embryo Uni-ZAP XR H0009 Human Fetal BrainUni-ZAP XR H0010 Human Fetal Hepatic Human Fetal Liver Liver Uni-ZAP XRH0011 Human Fetal Kidney Human Fetal Kidney Kidney Uni-ZAP XR H0012Human Fetal Kidney Human Fetal Kidney Kidney Uni-ZAP XR H0013 Human 8Week Whole Embryo Human 8 Week Old Embryo Embryo Uni-ZAP XR H0014 HumanGall Bladder Human Gall Bladder Gall Bladder Uni-ZAP XR H0015 Human GallBladder, fraction II Human Gall Bladder Gall Bladder Uni-ZAP XR H0018Human Greater Omentum, fII remake Human Greater Omentum peritoneumUni-ZAP XR H0019 Human Fetal Heart Human Fetal Heart Heart pBluescriptH0020 Human Hippocampus Human Hippocampus Brain Uni-ZAP XR H0021 HumanInfant Adrenal Gland Human Infant Adrenal Gland Adrenal gland Uni-ZAP XRH0022 Jurkat Cells Jurkat T-Cell Line Lambda ZAP II H0023 Human FetalLung Uni-ZAP XR H0024 Human Fetal Lung III Human Fetal Lung Lung Uni-ZAPXR H0025 Human Adult Lymph Node Human Adult Lymph Node Lymph Node LambdaZAP II H0026 Namalwa Cells Namalwa B-Cell Line, EBV Lambda ZAP IIimmortalized H0028 Human Old Ovary Human Old Ovary Ovary pBluescriptH0029 Human Pancreas Human Pancreas Pancreas Uni-ZAP XR H0030 HumanPlacenta Uni-ZAP XR H0031 Human Placenta Human Placenta Placenta Uni-ZAPXR H0032 Human Prostate Human Prostate Prostate Uni-ZAP XR H0033 HumanPituitary Human Pituitary Uni-ZAP XR H0035 Human Salivary Gland HumanSalivary Gland Salivary gland Uni-ZAP XR H0036 Human Adult SmallIntestine Human Adult Small Intestine Small Int. Uni-ZAP XR H0037 HumanAdult Small Intestine Human Adult Small Intestine Small Int. pBluescriptH0038 Human Testes Human Testes Testis Uni-ZAP XR H0039 Human PancreasTumor Human Pancreas Tumor Pancreas disease Uni-ZAP XR H0040 HumanTestes Tumor Human Testes Tumor Testis disease Uni-ZAP XR H0041 HumanFetal Bone Human Fetal Bone Bone Uni-ZAP XR H0042 Human Adult PulmonaryHuman Adult Pulmonary Lung Uni-ZAP XR H0044 Human Cornea Human Corneaeye Uni-ZAP XR H0045 Human Esophagus, Cancer Human Esophagus, cancerEsophagus disease Uni-ZAP XR H0046 Human Endometrial Tumor HumanEndometrial Tumor Uterus disease Uni-ZAP XR H0047 Human Fetal LiverHuman Fetal Liver Liver Uni-ZAP XR H0048 Human Pineal Gland Human PinealGland Uni-ZAP XR H0049 Human Fetal Kidney Human Fetal Kidney KidneyUni-ZAP XR H0050 Human Fetal Heart Human Fetal Heart Heart Uni-ZAP XRH0051 Human Hippocampus Human Hippocampus Brain Uni-ZAP XR H0052 HumanCerebellum Human Cerebellum Brain Uni-ZAP XR H0053 Human Adult KidneyHuman Adult Kidney Kidney Uni-ZAP XR H0056 Human Umbilical Vein, Endo.remake Human Umbilical Vein Umbilical vein Uni-ZAP XR Endothelial CellsH0057 Human Fetal Spleen Uni-ZAP XR H0058 Human Thymus Tumor HumanThymus Tumor Thymus disease Lambda ZAP II H0059 Human Uterine CancerHuman Uterine Cancer Uterus disease Lambda ZAP II H0060 Human MacrophageHuman Macrophage Blood Cell Line pBluescript H0061 Human MacrophageHuman Macrophage Blood Cell Line pBluescript H0062 Human Thymus HumanThymus Thymus Uni-ZAP XR H0063 Human Thymus Human Thymus Thymus Uni-ZAPXR H0064 Human Right Hemisphere of Brain Human Brain, right BrainUni-ZAP XR hemisphere H0067 Human left hemisphere, adult Human LeftHemisphere, Brain Lambda ZAP II Adult H0068 Human Skin Tumor Human SkinTumor Skin disease Uni-ZAP XR H0069 Human Activated T-Cells ActivatedT-Cells Blood Cell Line Uni-ZAP XR H0070 Human Pancreas Human PancreasPancreas Uni-ZAP XR H0071 Human Infant Adrenal Gland Human InfantAdrenal Gland Adrenal gland Uni-ZAP XR H0073 Human Leiomyeloid CarcinomaHuman Leiomyeloid Muscle disease Uni-ZAP XR Carcinoma H0074 HumanPlatelets Human Platelets Blood Cell Line Uni-ZAP XR H0075 HumanActivated T-Cells (II) Activated T-Cells Blood Cell Line Uni-ZAP XRH0077 Human Thymus Tumor Human Thymus Tumor Thymus disease Lambda ZAP IIH0078 Human Lung Cancer Human Lung Cancer Lung disease Lambda ZAP IIH0079 Human Whole 7 Week Old Embryo (II) Human Whole 7 Week Old EmbryoUni-ZAP XR Embryo H0080 Human Whole 6 Week Old Embryo (II) Human WholeSix Week Old Embryo Lambda ZAP II Embryo H0081 Human Fetal Epithelium(Skin) Human Fetal Skin Skin Uni-ZAP XR H0082 Human Fetal Muscle HumanFetal Muscle Sk Muscle Uni-ZAP XR H0083 HUMAN JURKAT MEMBRANE BOUNDJurkat Cells Uni-ZAP XR POLYSOMES H0085 Human Colon Human Colon LambdaZAP II H0086 Human epithelioid sarcoma Epithelioid Sarcoma, muscle SkMuscle disease Uni-ZAP XR H0087 Human Thymus Human Thymus pBluescriptH0090 Human T-Cell Lymphoma T-Cell Lymphoma T-Cell disease Uni-ZAP XRH0092 Human Pancreas Tumor Human Pancreas Tumor Pancreas disease Uni-ZAPXR H0093 Human Greater Omentum Tumor Human Greater Omentum peritoneumdisease Uni-ZAP XR H0095 Human Greater Omentum, RNA Remake Human GreaterOmentum peritoneum Uni-ZAP XR H0097 Human Adult Heart, subtracted HumanAdult Heart Heart pBluescript H0098 Human Adult Liver, subtracted HumanAdult Liver Liver Uni-ZAP XR H0099 Human Lung Cancer, subtracted HumanLung Cancer Lung pBluescript H0100 Human Whole Six Week Old Embryo HumanWhole Six Week Old Embryo Uni-ZAP XR Embryo H0101 Human 7 Weeks OldEmbryo, subtracted Human Whole 7 Week Old Embryo Lambda ZAP II EmbryoH0102 Human Whole 6 Week Old Embryo (II), subt Human Whole Six Week OldEmbryo pBluescript Embryo H0103 Human Fetal Brain, subtracted HumanFetal Brain Brain Uni-ZAP XR H0105 Human Fetal Heart, subtracted HumanFetal Heart Heart pBluescript H0107 Human Infant Adrenal Gland,subtracted Human Infant Adrenal Gland Adrenal gland pBluescript H0108Human Adult Lymph Node, subtracted Human Adult Lymph Node Lymph NodeUni-ZAP XR H0109 Human Macrophage, subtracted Macrophage Blood Cell LinepBluescript H0110 Human Old Ovary, subtracted Human Old Ovary OvarypBluescript H0111 Human Placenta, subtracted Human Placenta PlacentapBluescript H0113 Human skin Tumor, subtracted Human Skin Tumor SkinUni-ZAP XR H0116 Human Thymus Tumor, subtracted Human Thymus TumorThymus pBluescript H0117 Human Uterine Cancer, subtracted Human UterineCancer Uterus pBluescript H0119 Human Pediatric Kidney Human PediatricKidney Kidney Uni-ZAP XR H0120 Human Adult Spleen, subtracted HumanAdult Spleen Spleen Uni-ZAP XR H0121 Human Cornea, subtracted HumanCornea eye Uni-ZAP XR H0122 Human Adult Skeletal Muscle Human SkeletalMuscle Sk Muscle Uni-ZAP XR H0123 Human Fetal Dura Mater Human FetalDura Mater Brain Uni-ZAP XR H0124 Human Rhabdomyosarcoma HumanRhabdomyosarcoma Sk Muscle disease Uni-ZAP XR H0125 Cem cellscyclohexamide treated Cyclohexamide Treated Blood Cell Line Uni-ZAP XRCem, Jurkat, Raji, and Supt H0128 Jurkat cells, thiouridine activatedJurkat Cells Uni-ZAP XR H0129 Jurkat cells, thiouridine activated, fractII Jurkat Cells Uni-ZAP XR H0130 LNCAP untreated LNCAP Cell LineProstate Cell Line Uni-ZAP XR H0131 LNCAP + o.3 nM R1881 LNCAP Cell LineProstate Cell Line Uni-ZAP XR H0132 LNCAP + 30 nM R1881 LNCAP Cell LineProstate Cell Line Uni-ZAP XR H0134 Raji Cells, cyclohexamide treatedCyclohexamide Treated Blood Cell Line Uni-ZAP XR Cem, Jurkat, Raji, andSupt H0135 Human Synovial Sarcoma Human Synovial Sarcoma SynoviumUni-ZAP XR H0136 Supt Cells, cyclohexamide treated Cyclohexamide TreatedBlood Cell Line Uni-ZAP XR Cem, Jurkat, Raji, and Supt H0140 ActivatedT-Cells, 8 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0141Activated T-Cells, 12 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XRH0142 MCF7 Cell Line MCF7 Cell line Breast Cell Line Uni-ZAP XR H0144Nine Week Old Early Stage Human 9 Wk Old Early Stage Embryo Uni-ZAP XRHuman H0147 Human Adult Liver Human Adult Liver Liver Uni-ZAP XR H0149 7Week Old Early Stage Human, subtracted Human Whole 7 Week Old EmbryoUni-ZAP XR Embryo H0150 Human Epididymus Epididymis Testis Uni-ZAP XRH0151 Early Stage Human Liver Human Fetal Liver Liver Uni-ZAP XR H0152Early Stage Human Liver, fract (II) Human Fetal Liver Liver Uni-ZAP XRH0154 Human Fibrosarcoma Human Skin Fibrosarcoma Skin disease Uni-ZAP XRH0155 Human Thymus, subtracted Human Thymus Tumor Thymus pBluescriptH0156 Human Adrenal Gland Tumor Human Adrenal Gland Adrenal Glanddisease Uni-ZAP XR Tumor H0157 Activated T-Cells, 0 hrs, ligation 2Activated T-Cells Blood Cell Line Uni-ZAP XR H0158 Activated T-Cells, 4hrs., ligation 2 Activated T-Cells Blood Cell Line Uni-ZAP XR H0159Activated T-Cells, 8 hrs., ligation 2 Activated T-Cells Blood Cell LineUni-ZAP XR H0163 Human Synovium Human Synovium Synovium Uni-ZAP XR H0164Human Trachea Tumor Human Trachea Tumor Trachea disease Uni-ZAP XR H0165Human Prostate Cancer, Stage B2 Human Prostate Cancer, Prostate diseaseUni-ZAP XR stage B2 H0166 Human Prostate Cancer, Stage B2 fraction HumanProstate Cancer, Prostate disease Uni-ZAP XR stage B2 H0167 ActivatedT-Cells, 24 hrs. Activated T-Cells Blood Cell Line Uni-ZAP XR H0168Human Prostate Cancer, Stage C Human Prostate Cancer, Prostate diseaseUni-ZAP XR stage C H0169 Human Prostate Cancer, Stage C fraction HumanProstate Cancer, Prostate disease Uni-ZAP XR stage C H0170 12 Week OldEarly Stage Human Twelve Week Old Early Embryo Uni-ZAP XR Stage HumanH0171 12 Week Old Early Stage Human, II Twelve Week Old Early EmbryoUni-ZAP XR Stage Human H0172 Human Fetal Brain, random primed HumanFetal Brain Brain Lambda ZAP II H0173 Human Cardiomyopathy, RNA remakeHuman Cardiomyopathy Heart disease Uni-ZAP XR H0175 H. Adult Spleen,ziplox pSport1 H0176 CAMA1Ee Cell Line CAMA1Ee Cell Line Breast CellLine Uni-ZAP XR H0177 CAMA1Ee Cell Line CAMA1Ee Cell Line Breast CellLine Uni-ZAP XR H0178 Human Fetal Brain Human Fetal Brain Brain Uni-ZAPXR H0179 Human Neutrophil Human Neutrophil Blood Cell Line Uni-ZAP XRH0181 Human Primary Breast Cancer Human Primary Breast Breast diseaseUni-ZAP XR Cancer H0182 Human Primary Breast Cancer Human Primary BreastBreast disease Uni-ZAP XR Cancer H0183 Human Colon Cancer Human ColonCancer Colon disease Uni-ZAP XR H0184 Human Colon Cancer, metasticizedto live Human Colon Cancer, Liver disease Lambda ZAP II metasticized toliver H0185 Activated T-Cell labeled with 4-thioluri T-Cells Blood CellLine Lambda ZAP II H0186 Activated T-Cell T-Cells Blood Cell Line LambdaZAP II H0187 Resting T-Cell T-Cells Blood Cell Line Lambda ZAP II H0188Human Normal Breast Human Normal Breast Breast Uni-ZAP XR H0189 HumanResting Macrophage Human Blood Cell Line Uni-ZAP XR Macrophage/MonocytesH0190 Human Activated Macrophage (LPS) Human Blood Cell Line Uni-ZAP XRMacrophage/Monocytes H0191 Human Activated Macrophage (LPS), thiourHuman Blood Cell Line Uni-ZAP XR Macrophage/Monocytes H0192 Cem Cells,cyclohexamide treated, subtra Cyclohexamide Treated Blood Cell LineUni-ZAP XR Cem, Jurkat, Raji, and Supt H0193 Cem Cells, cyclohexamidetreated, differ Cyclohexamide Treated Blood Cell Line Uni-ZAP XR Cem,Jurkat, Raji, and Supt H0194 Human Cerebellum, subtracted HumanCerebellum Brain pBluescript H0196 Human Cardiomyopathy, subtractedHuman Cardiomyopathy Heart Uni-ZAP XR H0197 Human Fetal Liver,subtracted Human Fetal Liver Liver Uni-ZAP XR H0198 Human Fetal Liver,subtracted, pos. clon Human Fetal Liver Liver Uni-ZAP XR H0199 HumanFetal Liver, subtracted, neg clone Human Fetal Liver Liver Uni-ZAP XRH0200 Human Greater Omentum, fract II remake, Human Greater Omentumperitoneum Uni-ZAP XR H0201 Human Hippocampus, subtracted HumanHippocampus Brain pBluescript H0202 Jurkat Cells, cyclohexamide treated,Cyclohexamide Treated Blood Cell Line Uni-ZAP XR subtraction Cem,Jurkat, Raji, and Supt H0203 Jurkat Cells, cyclohexamide treated, difCyclohexamide Treated Blood Cell Line Uni-ZAP XR Cem, Jurkat, Raji, andSupt H0204 Human Colon Cancer, subtracted Human Colon Cancer ColonpBluescript H0205 Human Colon Cancer, differential Human Colon CancerColon pBluescript H0207 LNCAP, differential expression LNCAP Cell LineProstate Cell Line pBluescript H0208 Early Stage Human Lung, subtractedHuman Fetal Lung Lung pBluescript H0209 Human Cerebellum, differentiallyexpressed Human Cerebellum Brain Uni-ZAP XR H0211 Human Prostate,differential expression Human Prostate Prostate pBluescript H0212 HumanProstate, subtracted Human Prostate Prostate pBluescript H0213 HumanPituitary, subtracted Human Pituitary Uni-ZAP XR H0214 Raji cells,cyclohexamide treated, subtracted Cyclohexamide Treated Blood Cell LinepBluescript Cem, Jurkat, Raji, and Supt H0215 Raji cells, cyclohexamidetreated, Cyclohexamide Treated Blood Cell Line pBluescriptdifferentially expressed Cem, Jurkat, Raji, and Supt H0216 Supt cells,cyclohexamide treated, subtracted Cyclohexamide Treated Blood Cell LinepBluescript Cem, Jurkat, Raji, and Supt H0217 Supt cells, cyclohexamidetreated, Cyclohexamide Treated Blood Cell Line pBluescriptdifferentially expressed Cem, Jurkat, Raji, and Supt H0218 ActivatedT-Cells, 0 hrs, subtracted Activated T-Cells Blood Cell Line Uni-ZAP XRH0219 Activated T-Cells, 0 hrs, differentially Activated T-Cells BloodCell Line Uni-ZAP XR expressed H0220 Activated T-Cells, 4 hrs,subtracted Activated T-Cells Blood Cell Line Uni-ZAP XR H0222 ActivatedT-Cells, 8 hrs, subtracted Activated T-Cells Blood Cell Line Uni-ZAP XRH0224 Activated T-Cells, 12 hrs, subtracted Activated T-Cells Blood CellLine Uni-ZAP XR H0225 Activated T-Cells, 12 hrs, differentiallyActivated T-Cells Blood Cell Line Uni-ZAP XR expressed H0228 C7MCF7 cellline, estrogen treated C7MCF7 Cell Line, estrogen Breast Cell LineUni-ZAP XR treated H0229 Early Stage Human Brain, random primed EarlyStage Human Brain Brain Lambda ZAP II H0230 Human Cardiomyopathy, diffexp Human Cardiomyopathy Heart disease Uni-ZAP XR H0231 Human Colon,subtraction Human Colon pBluescript H0232 Human Colon, differentialexpression Human Colon pBluescript H0233 Human Fetal Heart, Differential(Adult- Human Fetal Heart Heart pBluescript Specific) H0234 human coloncancer, metastatic to liver, Human Colon Cancer, Liver pBluescriptdifferentially expressed metasticized to liver H0235 Human colon cancer,metaticized to liver, Human Colon Cancer, Liver pBluescript subtractionmetasticized to liver H0239 Human Kidney Tumor Human Kidney Tumor Kidneydisease Uni-ZAP XR H0241 C7MCF7 cell line, estrogen treated, C7MCF7 CellLine, estrogen Breast Cell Line Uni-ZAP XR subtraction treated H0242Human Fetal Heart, Differential (Fetal- Human Fetal Heart HeartpBluescript Specific) H0244 Human 8 Week Whole Embryo, subtracted Human8 Week Old Embryo Embryo Uni-ZAP XR H0246 Human Fetal Liver- Enzymesubtraction Human Fetal Liver Liver Uni-ZAP XR H0247 Human MembraneBound Polysomes- Human Membrane Bound Blood Cell Line Uni-ZAP XR EnzymeSubtraction Polysomes H0249 HE7, subtracted by hybridization with E7Human Whole 7 Week Old Embryo Uni-ZAP XR cDNA Embryo H0250 HumanActivated Monocytes Human Monocytes Uni-ZAP XR H0251 HumanChondrosarcoma Human Chondrosarcoma Cartilage disease Uni-ZAP XR H0252Human Osteosarcoma Human Osteosarcoma Bone disease Uni-ZAP XR H0253Human adult testis, large inserts Human Adult Testis Testis Uni-ZAP XRH0254 Breast Lymph node cDNA library Breast Lymph Node Lymph NodeUni-ZAP XR H0255 breast lymph node CDNA library Breast Lymph Node LymphNode Lambda ZAP II H0256 HL-60, unstimulated Human HL-60 Cells, BloodCell Line Uni-ZAP XR unstimulated H0257 HL-60, PMA 4 H HL-60 Cells, PMABlood Cell Line Uni-ZAP XR stimulated 4 H H0261 H. cerebellum, Enzymesubtracted Human Cerebellum Brain Uni-ZAP XR H0263 human colon cancerHuman Colon Cancer Colon disease Lambda ZAP II H0264 human tonsils HumanTonsil Tonsil Uni-ZAP XR H0265 Activated T-Cell (12 hs)/ThiouridineT-Cells Blood Cell Line Uni-ZAP XR labelledEco H0266 Human MicrovascularEndothelial Cells, HMEC Vein Cell Line Lambda ZAP II fract. A H0267Human Microvascular Endothelial Cells, HMEC Vein Cell Line Lambda ZAP IIfract. B H0268 Human Umbilical Vein Endothelial Cells, HUVE CellsUmbilical vein Cell Line Lambda ZAP II fract. A H0269 Human UmbilicalVein Endothelial Cells, HUVE Cells Umbilical vein Cell Line Lambda ZAPII fract. B H0270 HPAS (human pancreas, subtracted) Human PancreasPancreas Uni-ZAP XR H0271 Human Neutrophil, Activated Human Neutrophil -Blood Cell Line Uni-ZAP XR Activated H0272 HUMAN TONSILS, FRACTION 2Human Tonsil Tonsil Uni-ZAP XR H0274 Human Adult Spleen, fractionIIHuman Adult Spleen Spleen Uni-ZAP XR H0275 Human Infant Adrenal Gland,Subtracted Human Infant Adrenal Gland Adrenal gland pBluescript H0279K562 cells K562 Cell line cell line Cell Line ZAP Express H0280 K562 +PMA (36 hrs) K562 Cell line cell line Cell Line ZAP Express H0281 Lymphnode, abnorm. cell line (ATCC Lymph Node, abnormal cell Lymph Node CellLine ZAP Express #7225) line H0282 HBGB''s differential consolidationHuman Primary Breast Breast Uni-ZAP XR Cancer H0284 Human OB MG63control fraction I Human Osteoblastoma Bone Cell Line Uni-ZAP XR MG63cell line H0286 Human OB MG63 treated (10 nM E2) Human OsteoblastomaBone Cell Line Uni-ZAP XR fraction I MG63 cell line H0288 Human OB HOScontrol fraction I Human Osteoblastoma HOS Bone Cell Line Uni-ZAP XRcell line H0290 Human OB HOS treated (1 nM E2) fraction I HumanOsteoblastoma HOS Bone Cell Line Uni-ZAP XR cell line H0292 Human OB HOStreated (10 nM E2) Human Osteoblastoma HOS Bone Cell Line Uni-ZAP XRfraction I cell line H0293 WI 38 cells Uni-ZAP XR H0294 Amniotic Cells -TNF induced Amniotic Cells - TNF Placenta Cell Line Uni-ZAP XR inducedH0295 Amniotic Cells - Primary Culture Amniotic Cells - Primary PlacentaCell Line Uni-ZAP XR Culture H0298 HCBB''s differential consolidationCAMA1Ee Cell Line Breast Cell Line Uni-ZAP XR H0299 HCBA''s differentialconsolidation CAMA1Ee Cell Line Breast Cell Line Uni-ZAP XR H0300 CD34positive cells (Cord Blood) CD34 Positive Cells Cord Blood ZAP ExpressH0305 CD34 positive cells (Cord Blood) CD34 Positive Cells Cord BloodZAP Express H0306 CD34 depleted Buffy Coat (Cord Blood) CD34 DepletedBuffy Coat Cord Blood ZAP Express (Cord Blood) H0309 Human ChronicSynovitis Synovium, Chronic Synovium disease Uni-ZAP XRSynovitis/Osteoarthritis H0310 human caudate nucleus Brain Brain Uni-ZAPXR H0313 human pleural cancer pleural cancer disease pBluescript H0316HUMAN STOMACH Human Stomach Stomach Uni-ZAP XR H0318 HUMAN B CELLLYMPHOMA Human B Cell Lymphoma Lymph Node disease Uni-ZAP XR H0320 Humanfrontal cortex Human Frontal Cortex Brain Uni-ZAP XR H0321 HUMANSCHWANOMA Schwanoma Nerve disease Uni-ZAP XR H0327 human corpus colosumHuman Corpus Callosum Brain Uni-ZAP XR H0328 human ovarian cancerOvarian Cancer Ovary disease Uni-ZAP XR H0329 DermatofibrosarcomaProtuberance Dermatofibrosarcoma Skin disease Uni-ZAP XR ProtuberansH0330 HCBB''s Subtractive (-mito genes) CAMA1Ee Cell Line Breast CellLine Uni-ZAP XR H0331 Hepatocellular Tumor Hepatocellular Tumor Liverdisease Lambda ZAP II H0333 Hemangiopericytoma Hemangiopericytoma Bloodvessel disease Lambda ZAP II H0334 Kidney cancer Kidney Cancer Kidneydisease Uni-ZAP XR H0339 Duodenum Duodenum Uni-ZAP XR H0340 CorpusCallosum Corpus Collosum-93052 Uni-ZAP XR H0341 Bone Marrow Cell Line(RS4; 11) Bone Marrow Cell Line Bone Marrow Cell Line Uni-ZAP XR RS4; 11H0342 Lingual Gyrus Lingual Gyrus Brain Uni-Zap XR H0343 stomach cancer(human) Stomach Cancer - 5383A disease Uni-ZAP XR (human) H0344 Adiposetissue (human) Adipose - 6825A (human) Uni-ZAP XR H0345 SKIN Skin -4000868H Skin Uni-ZAP XR H0346 Brain-medulloblastoma Brain(Medulloblastoma)- Brain disease Uni-ZAP XR 9405C006R H0349 human adultliver cDNA library Human Adult Liver Liver pCMVSport 1 H0350 Human FetalLiver, mixed 10 & 14 week Human Fetal Liver, mixed Liver Uni-ZAP XR10&14 Week H0351 Glioblastoma Glioblastoma Brain disease Uni-ZAP XRH0352 wilm''s tumor Wilm''s Tumor disease Uni-ZAP XR H0354 HumanLeukocytes Human Leukocytes Blood Cell Line pCMVSport 1 H0355 HumanLiver Human Liver, normal Adult pCMVSport 1 H0356 Human Kidney HumanKidney Kidney pCMVSport 1 H0357 H. Normalized Fetal Liver, II HumanFetal Liver Liver Uni-ZAP XR H0359 KMH2 cell line KMH2 ZAP Express H0360Hemangiopericytoma Hemangiopericytoma disease H0361 Human rejectedkidney Human Rejected Kidney disease pBluescript H0362 HeLa cell lineHELA CELL LINE pSport1 H0363 Human Brain Medulla, subtracted Human BrainMedulla pBluescript H0364 Human Osteoclastoma, excised HumanOsteoclastoma disease pBluescript H0365 Osteoclastoma-normalized B HumanOsteoclastoma disease Uni-ZAP XR H0366 L428 cell line L428 ZAP ExpressH0369 H. Atrophic Endometrium Atrophic Endometrium and Uni-ZAP XRmyometrium H0370 H. Lymph node breast Cancer Lymph node with Met.disease Uni-ZAP XR Breast Cancer H0371 Eosinophils-Hypereosinophiliapatient Eosinophils- disease Uni-ZAP XR Hypereosinophilia patient H0372Human Testes Human Testes Testis pCMVSport 1 H0373 Human Heart HumanAdult Heart Heart pCMVSport 1 H0374 Human Brain Human Brain pCMVSport 1H0375 Human Lung Human Lung pCMVSport 1 H0376 Human Spleen Human AdultSpleen Spleen pCMVSport 1 H0379 Human Tongue, frac 1 Human TonguepSport1 H0380 Human Tongue, frac 2 Human Tongue pSport1 H0381 BoneCancer Bone Cancer disease Uni-ZAP XR H0383 Human Prostate BPH,re-excision Human Prostate BPH Uni-ZAP XR H0384 Brain, Kozak Human BrainpCMVSport 1 H0385 H. Leukocytes, Kozak Human Leukocytes Blood Cell LinepCMVSport 1 H0386 Leukocyte and Lung; 4 screens Human Leukocytes BloodCell Line pCMVSport 1 H0388 Human Rejected Kidney, 704 re-excision HumanRejected Kidney disease pBluescript H0389 H. Brain, X-Chromosomehybridization Human Brain pCMVSport 1 H0390 Human Amygdala Depression,re-excision Human Amygdala disease pBluescript Depression H0391 H.Meniingima, M6 Human Meningima brain pSport1 H0392 H. Meningima, M1Human Meningima brain pSport1 H0393 Fetal Liver, subtraction II HumanFetal Liver Liver pBluescript H0394 A-14 cell line Redd-Sternberg cellZAP Express H0395 A1-CELL LINE Redd-Sternberg cell ZAP Express H0396 L1Cell line Redd-Sternberg cell ZAP Express H0398 Human Newborn BladderHuman Newborn Bladder pBluescript H0399 Human Kidney Cortex, re-rescueHuman Kidney Cortex Lambda ZAP II H0400 Human Striatum Depression,re-rescue Human Brain, Striatum Brain Lambda ZAP II Depression H0401Human Pituitary, subtracted V Human Pituitary pBluescript H0402 CD34depleted Buffy Coat (Cord Blood), re- CD34 Depleted Buffy Coat CordBlood ZAP Express excision (Cord Blood) H0403 H. Umbilical VeinEndothelial Cells, IL4 HUVE Cells Umbilical vein Cell Line Uni-ZAP XRinduced H0404 H. Umbilical Vein endothelial cells, HUVE Cells Umbilicalvein Cell Line Uni-ZAP XR uninduced H0405 Human Pituitary, subtracted VIHuman Pituitary pBluescript H0406 H Amygdala Depression, subtractedHuman Amygdala Uni-ZAP XR Depression H0408 Human kidney Cortex,subtracted Human Kidney Cortex pBluescript H0409 H. Striatum Depression,subtracted Human Brain, Striatum Brain pBluescript Depression H0410 H.Male bladder, adult H Male Bladder, Adult Bladder pSport1 H0411 H FemaleBladder, Adult Human Female Adult Bladder pSport1 Bladder H0412 Humanumbilical vein endothelial cells, IL-4 HUVE Cells Umbilical vein CellLine pSport1 induced H0413 Human Umbilical Vein Endothelial Cells, HUVECells Umbilical vein Cell Line pSport1 uninduced H0414 Ovarian Tumor I,OV5232 Ovarian Tumor, OV5232 Ovary disease pSport1 H0415 H. OvarianTumor, II, OV5232 Ovarian Tumor, OV5232 Ovary disease pCMVSport 2.0H0416 Human Neutrophils, Activated, re-excision Human Neutrophil - BloodCell Line pBluescript Activated H0417 Human Pituitary, subtracted VIIIHuman Pituitary pBluescript H0418 Human Pituitary, subtracted VII HumanPituitary pBluescript H0419 Bone Cancer, re-excision Bone Cancer Uni-ZAPXR H0421 Human Bone Marrow, re-excision Bone Marrow pBluescript H0422T-Cell PHA 16 hrs T-Cells Blood Cell Line pSport1 H0423 T-Cell PHA 24hrs T-Cells Blood Cell Line pSport1 H0424 Human Pituitary, subt IX HumanPituitary pBluescript H0427 Human Adipose Human Adipose, left pSport1hiplipoma H0428 Human Ovary Human Ovary Tumor Ovary pSport1 H0429 K562 +PMA (36 hrs), re-excision K562 Cell line cell line Cell Line ZAP ExpressH0431 H. Kidney Medulla, re-excision Kidney medulla Kidney pBluescriptH0432 H. Kidney Pyramid Kidney pyramids Kidney pBluescript H0433 HumanUmbilical Vein HUVE Cells Umbilical vein Cell Line pBluescriptEndothelial cells, frac B, re-excision H0434 Human Brain, striatum,re-excision Human Brain, Striatum pBluescript H0435 Ovarian Tumor10-3-95 Ovarian Tumor, OV350721 Ovary pCMVSport 2.0 H0436 Resting T-CellLibrary, II T-Cells Blood Cell Line pSport1 H0437 H Umbilical VeinEndothelial Cells, frac A, HUVE Cells Umbilical vein Cell Line LambdaZAP II re-excision H0438 H. Whole Brain #2, re-excision Human WholeBrain #2 ZAP Express H0439 Human Eosinophils Eosinophils pBluescriptH0440 FGF enriched mixed library Mixed libraries pCMVSport 1 H0441 H.Kidney Cortex, subtracted Kidney cortex Kidney pBluescript H0442 H.Striatum Depression, subt II Human Brain, Striatum Brain pBluescriptDepression H0443 H. Adipose, subtracted Human Adipose, left pSport1hiplipoma H0444 Spleen metastic melanoma Spleen, Metastic malignantSpleen disease pSport1 melanoma H0445 Spleen, Chronic lymphocyticleukemia Human Spleen, CLL Spleen disease pSport1 H0447 Salivary gland,re-excision Human Salivary Gland Salivary gland Uni-ZAP XR H0448Salivary gland, subtracted Human Salivary Gland Salivary gland LambdaZAP II H0449 CD34 + cell, I CD34 positive cells pSport1 H0450 CD34+cells, II CD34 positive cells pCMVSport 2.0 H0453 H. Kidney Pyramid,subtracted Kidney pyramids Kidney pBluescript H0455 H. StriatumDepression, subt Human Brain, Striatum Brain pBluescript DepressionH0456 H Kidney Cortex, subtracted III Human Kidney Cortex pBluescriptH0457 Human Eosinophils Human Eosinophils pSport1 H0458 CD34 + cell, I,frac II CD34 positive cells pSport1 H0459 CD34+cells, II, FRACTION 2CD34 positive cells pCMVSport 2.0 H0461 H. Kidney Medulla, subtractedKidney medulla Kidney pBluescript H0462 H. Amygdala Depression,subtracted Brain pBluescript H0477 Human Tonsil, Lib 3 Human TonsilTonsil pSport1 H0478 Salivary Gland, Lib 2 Human Salivary Gland Salivarygland pSport1 H0479 Salivary Gland, Lib 3 Human Salivary Gland Salivarygland pSport1 H0480 L8 cell line L8 cell line ZAP Express H0483 BreastCancer cell line, MDA 36 Breast Cancer Cell line, pSport1 MDA 36 H0484Breast Cancer Cell line, angiogenic Breast Cancer Cell line, pSport1Angiogenic, 36T3 H0485 Hodgkin''s Lymphoma I Hodgkin''s Lymphoma Idisease pCMVSport 2.0 H0486 Hodgkin''s Lymphoma II Hodgkin''s LymphomaII disease pCMVSport 2.0 H0487 Human Tonsils, lib I Human TonsilspCMVSport 2.0 H0488 Human Tonsils, Lib 2 Human Tonsils pCMVSport 2.0H0489 Crohn''s Disease Ileum Intestine disease pSport1 H0490 HI-60,untreated, subtracted Human HL-60 Cells, Blood Cell Line Uni-ZAP XRunstimulated H0491 HL-60, PMA 4 H, subtracted HL-60 Cells, PMA BloodCell Line Uni-ZAP XR stimulated 4 H H0492 HL-60, RA 4 h, SubtractedHL-60 Cells, RA stimulated Blood Cell Line Uni-ZAP XR for 4 H H0493HL-60, PMA 1 d, subtracted HL-60 Cells, PMA Blood Cell Line Uni-ZAP XRstimulated for 1 day H0494 Keratinocyte Keratinocyte pCMVSport 2.0 H0497HEL cell line HEL cell line HEL 92.1.7 pSport1 H0505 Human AstrocyteHuman Astrocyte pSport1 H0506 Ulcerative Colitis Colon Colon pSport1H0509 Liver, Hepatoma Human Liver, Hepatoma, Liver disease pCMVSport 3.0patient 8 H0510 Human Liver, normal Human Liver, normal, Liver pCMVSport3.0 Patient # 8 H0512 Keratinocyte, lib 3 Keratinocyte pCMVSport 2.0H0517 Nasal polyps Nasal polyps pCMVSport 2.0 H0518 pBMC stimulated w/poly I/C pBMC stimulated with poly pCMVSport 3.0 I/C H0519 NTERA2,control NTERA2, Teratocarcinoma pCMVSport 3.0 cell line H0520 NTERA2 +retinoic acid, 14 days NTERA2, Teratocarcinoma pSport1 cell line H0521Primary Dendritic Cells, lib 1 Primary Dendritic cells pCMVSport 3.0H0522 Primary Dendritic cells, frac 2 Primary Dendritic cells pCMVSport3.0 H0523 Primary Dendritic cells, CapFinder2, frac 1 Primary Dendriticcells pSport1 H0524 Primary Dendritic Cells, CapFinder, frac 2 PrimaryDendritic cells pSport1 H0525 PCR, pBMC I/C treated pBMC stimulated withpoly PCRII I/C H0528 Poly[I]/Poly[C] Normal Lung FibroblastsPoly[I]/Poly[C] Normal pCMVSport 3.0 Lung Fibroblasts H0529 MyoloidProgenitor Cell Line TF-1 Cell Line; Myoloid pCMVSport 3.0 progenitorcell line H0530 Human Dermal Endothelial Cells, untreated Human DermalEndothelial pSport1 Cells; untreated H0535 Human ovary tumor cellOV350721 Ovarian Tumor, OV350721 Ovary disease pSport1 H0537 H. PrimaryDendritic Cells, lib 3 Primary Dendritic cells pCMVSport 2.0 H0538Merkel Cells Merkel cells Lymph node pSport1 H0539 Pancreas Islet CellTumor Pancreas Islet Cell Tumour Pancreas disease pSport1 H0540 Skin,burned Skin, leg burned Skin pSport1 H0542 T Cell helper I Helper T cellpCMVSport 3.0 H0543 T cell helper II Helper T cell pCMVSport 3.0 H0544Human endometrial stromal cells Human endometrial stromal pCMVSport 3.0cells H0545 Human endometrial stromal Human endometrial stromalpCMVSport 3.0 cells-treated with progesterone cells-treated with progeH0546 Human endometrial stromal Human endometrial stromal pCMVSport 3.0cells-treated with estradiol cells-treated with estra H0547 NTERA2teratocarcinoma cell line + retinoic NTERA2, Teratocarcinoma pSport1acid (14 days) cell line H0549 H. Epididiymus, caput & corpus HumanEpididiymus, caput Uni-ZAP XR and corpus H0550 H. Epididiymus, caudaHuman Epididiymus, cauda Uni-ZAP XR H0551 Human Thymus Stromal CellsHuman Thymus Stromal pCMVSport 3.0 Cells H0552 Signal trap, Femur BoneMarrow, pooled Femur Bone marrow, pooled Other from 8 male/female H0553Human Placenta Human Placenta pCMVSport 3.0 H0555 Rejected Kidney, lib 4Human Rejected Kidney Kidney disease pCMVSport 3.0 H0556 ActivatedT-cell(12 h)/Thiouridine-re- T-Cells Blood Cell Line Uni-ZAP XR excisionH0559 HL-60, PMA 4 H, re-excision HL-60 Cells, PMA Blood Cell LineUni-ZAP XR stimulated 4 H H0560 KMH2 KMH2 pCMVSport 3.0 H0561 L428 L428pCMVSport 3.0 H0562 Human Fetal Brain, normalized c5-11-26 Human FetalBrain pCMVSport 2.0 H0563 Human Fetal Brain, normalized 50021F HumanFetal Brain pCMVSport 2.0 H0564 Human Fetal Brain, normalized C5001FHuman Fetal Brain pCMVSport 2.0 H0565 HUman Fetal Brain, normalized100024F Human Fetal Brain pCMVSport 2.0 H0566 Human Fetal Brain,normalized c50F Human Fetal Brain pCMVSport 2.0 H0567 Human Fetal Brain,normalized A5002F Human Fetal Brain pCMVSport 2.0 H0569 Human FetalBrain, normalized CO Human Fetal Brain pCMVSport 2.0 H0570 Human FetalBrain, normalized C500H Human Fetal Brain pCMVSport 2.0 H0571 HumanFetal Brain, normalized C500HE Human Fetal Brain pCMVSport 2.0 H0572Human Fetal Brain, normalized AC5002 Human Fetal Brain pCMVSport 2.0H0574 Hepatocellular Tumor; re-excision Hepatocellular Tumor Liverdisease Lambda ZAP II H0575 Human Adult Pulmonary; re-excision HumanAdult Pulmonary Lung Uni-ZAP XR H0576 Resting T-Cell; re-excisionT-Cells Blood Cell Line Lambda ZAP II H0578 Human Fetal Thymus FetalThymus Thymus pSport1 H0579 Pericardium Pericardium Heart pSport1 H0580Dendritic cells, pooled Pooled dendritic cells pCMVSport 3.0 H0581 HumanBone Marrow, treated Human Bone Marrow Bone Marrow pCMVSport 3.0 H0583 BCell lymphoma B Cell Lymphoma B Cell disease pCMVSport 3.0 H0584Activated T-cells, 24 hrs, re-excision Activated T-Cells Blood Cell LineUni-ZAP XR H0585 Activated T-Cells, 12 hrs, re-excision ActivatedT-Cells Blood Cell Line Uni-ZAP XR H0586 Healing groin wound, 6.5 hourspost incision healing groin wound, 6.5 groin disease pCMVSport 3.0 hourspost incision - 2/ H0587 Healing groin wound; 7.5 hours post incisionGroin-2/19/97 groin disease pCMVSport 3.0 H0589 CD34 positive cells(cord blood), re-ex CD34 Positive Cells Cord Blood ZAP Express H0590Human adult small intestine, re-excision Human Adult Small IntestineSmall Int. Uni-ZAP XR H0591 Human T-cell lymphoma; re-excision T-CellLymphoma T-Cell disease Uni-ZAP XR H0592 Healing groin wound - zero hrpost-incision HGS wound healing project; disease pCMVSport 3.0 (control)abdomen H0593 Olfactory epithelium; nasalcavity Olfactory epitheliumfrom pCMVSport 3.0 roof of left nasal cacit H0594 Human Lung Cancer;re-excision Human Lung Cancer Lung disease Lambda ZAP II H0595 Stomachcancer (human); re-excision Stomach Cancer - 5383A disease Uni-ZAP XR(human) H0596 Human Colon Cancer; re-excision Human Colon Cancer ColonLambda ZAP II H0597 Human Colon; re-excision Human Colon Lambda ZAP IIH0598 Human Stomach; re-excision Human Stomach Stomach Uni-ZAP XR H0599Human Adult Heart; re-excision Human Adult Heart Heart Uni-ZAP XR H0600Healing Abdomen wound; 70&90 min post Abdomen disease pCMVSport 3.0incision H0601 Healing Abdomen Wound; 15 days post Abdomen diseasepCMVSport 3.0 incision H0602 Healing Abdomen Wound; 21&29 days postAbdomen disease pCMVSport 3.0 incision H0604 Human Pituitary,re-excision Human Pituitary pBluescript H0606 Human Primary BreastCancer; re-excision Human Primary Breast Breast disease Uni-ZAP XRCancer H0607 H. Leukocytes, normalized cot 50A3 H. Leukocytes pCMVSport1 H0608 H. Leukocytes, control H. Leukocytes pCMVSport 1 H0609 H.Leukocytes, normalized cot >500A H. Leukocytes pCMVSport 1 H0610 H.Leukocytes, normalized cot 5A H. Leukocytes pCMVSport 1 H0611 H.Leukocytes, normalized cot 500 B H. Leukocytes pCMVSport 1 H0612 H.Leukocytes, normalized cot 50 B H. Leukocytes pCMVSport 1 H0613 H.Leukocytes, normalized cot 5B H. Leukocytes pCMVSport 1 H0614 H.Leukocytes, normalized cot 500 A H. Leukocytes pCMVSport 1 H0615 HumanOvarian Cancer Reexcision Ovarian Cancer Ovary disease Uni-ZAP XR H0616Human Testes, Reexcision Human Testes Testis Uni-ZAP XR H0617 HumanPrimary Breast Cancer Reexcision Human Primary Breast Breast diseaseUni-ZAP XR Cancer H0618 Human Adult Testes, Large Inserts, Human AdultTestis Testis Uni-ZAP XR Reexcision H0619 Fetal Heart Human Fetal HeartHeart Uni-ZAP XR H0620 Human Fetal Kidney; Reexcision Human Fetal KidneyKidney Uni-ZAP XR H0622 Human Pancreas Tumor; Reexcision Human PancreasTumor Pancreas disease Uni-ZAP XR H0623 Human Umbilical Vein; ReexcisionHuman Umbilical Vein Umbilical vein Uni-ZAP XR Endothelial Cells H062412 Week Early Stage Human II; Reexcision Twelve Week Old Early EmbryoUni-ZAP XR Stage Human H0625 Ku 812F Basophils Line Ku812F BasophilspSport1 H0626 Saos2 Cells; Untreated Saos2 Cell Line; Untreated pSport1H0627 Saos2 Cells; Vitamin D3 Treated Saos2 Cell Line; Vitamin D3pSport1 Treated H0628 Human Pre-Differentiated Adipocytes HumanPre-Differentiated Uni-ZAP XR Adipocytes H0629 Human Leukocyte, control#2 Human Normalized pCMVSport 1 leukocyte H0630 Human Leukocytes,normalized control #4 Human Normalized pCMVSport 1 leukocyte H0631Saos2, Dexamethosome Treated Saos2 Cell Line; pSport1 DexamethosomeTreated H0632 Hepatocellular Tumor; re-excision Hepatocellular TumorLiver Lambda ZAP II H0633 Lung Carcinoma A549 TNFalpha activatedTNFalpha activated A549- disease pSport1 Lung Carcinoma H0634 HumanTestes Tumor, re-excision Human Testes Tumor Testis disease Uni-ZAP XRH0635 Human Activated T-Cells, re-excision Activated T-Cells Blood CellLine Uni-ZAP XR H0637 Dendritic Cells From CD34 Cells Dentritic cellsfrom CD34 pSport1 cells H0638 CD40 activated monocyte dendridic cellsCD40 activated monocyte pSport1 dendridic cells H0639 Ficolled HumanStromal Cells, 5Fu treated Ficolled Human Stromal Other Cells, 5Futreated H0640 Ficolled Human Stromal Cells, Untreated Ficolled HumanStromal Other Cells, Untreated H0641 LPS activated derived dendriticcells LPS activated monocyte pSport1 derived dendritic cells H0642 HepG2 Cells, lambda library Hep G2 Cells Other H0643 Hep G2 Cells, PCRlibrary Hep G2 Cells Other H0644 Human Placenta (re-excision) HumanPlacenta Placenta Uni-ZAP XR H0645 Fetal Heart, re-excision Human FetalHeart Heart Uni-ZAP XR H0646 Lung, Cancer (4005313 A3): InvasiveMetastatic squamous cell pSport1 Poorly Differentiated LungAdenocarcinoma, lung carcinoma, poorly di H0647 Lung, Cancer (4005163B7): Invasive, Invasive poorly disease pSport1 Poorly Diff.Adenocarcinoma, Metastatic differentiated lung adenocarcinoma H0648Ovary, Cancer: (4004562 B6) Papillary Papillary Cstic neoplasm ofdisease pSport1 Serous Cystic Neoplasm, Low Malignant Pot low malignantpotentia H0649 Lung, Normal: (4005313 B1) Normal Lung pSport1 H0650B-Cells B-Cells pCMVSport 3.0 H0651 Ovary, Normal: (9805C040R) NormalOvary pSport1 H0652 Lung, Normal: (4005313 B1) Normal Lung pSport1 H0653Stromal Cells Stromal Cells pSport1 H0654 Lung, Cancer: (4005313 A3)Invasive Metastatic Squamous cell Other Poorly-differentiated Metastaticlung adenoc lung Carcinoma poorly dif H0656 B-cells (unstimulated)B-cells (unstimulated) pSport1 H0657 B-cells (stimulated) B-cells(stimulated) pSport1 H0658 Ovary, Cancer (9809C332): Poorly 9809C332-Poorly Ovary & disease pSport1 differentiated adenocarcinomadifferentiate Fallopian Tubes H0659 Ovary, Cancer (15395A1F): Grade IIGrade II Papillary Ovary disease pSport1 Papillary Carcinoma Carcinoma,Ovary H0660 Ovary, Cancer: (15799A1F) Poorly Poorly differentiateddisease pSport1 differentiated carcinoma carcinoma, ovary H0661 Breast,Cancer: (4004943 A5) Breast cancer disease pSport1 H0662 Breast, Normal:(4005522B2) Normal Breast - Breast pSport1 #4005522(B2) H0663 Breast,Cancer: (4005522 A2) Breast Cancer - Breast disease pSport1 #4005522(A2)H0664 Breast, Cancer: (9806C012R) Breast Cancer Breast disease pSport1H0665 Stromal cells 3.88 Stromal cells 3.88 pSport1 H0666 Ovary, Cancer:(4004332 A2) Ovarian Cancer, Sample disease pSport1 #4004332A2 H0667Stromal cells(HBM3.18) Stromal cell(HBM 3.18) pSport1 H0668 stromal cellclone 2.5 stromal cell clone 2.5 pSport1 H0669 Breast, Cancer: (4005385A2) Breast Cancer (4005385A2) Breast pSport1 H0670 Ovary, Cancer(4004650A3): Well- Ovarian Cancer - pSport1 Differentiated Micropapillary Serous4004650A3 Carcinoma H0671 Breast, Cancer: (9802C02OE) Breast Cancer-Sample # pSport1 9802C02OE H0672 Ovary, Cancer: (4004576 A8) OvarianCancer(4004576A8) Ovary pSport1 H0673 Human Prostate Cancer, Stage B2;re- Human Prostate Cancer, Prostate Uni-ZAP XR excision stage B2 H0674Human Prostate Cancer, Stage C; re- Human Prostate Cancer, ProstateUni-ZAP XR excission stage C H0675 Colon, Cancer: (9808C064R) ColonCancer 9808C064R pCMVSport 3.0 H0676 Colon, Cancer: (9808C064R)-totalRNA Colon Cancer 9808C064R pCMVSport 3.0 H0677 TNFR degenerate oligoB-Cells PCRII H0678 screened clones from placental library PlacentaPlacenta Other H0679 screened clones from Tonsil library Human TonsilsOther H0682 Serous Papillary Adenocarcinoma serous papillary pCMVSport3.0 adenocarcinoma (9606G304SPA3B) H0683 Ovarian Serous PapillaryAdenocarcinoma Serous papillary pCMVSport 3.0 adenocarcinoma, stage 3C(9804G01 H0684 Serous Papillary Adenocarcinoma Ovarian Cancer-9810G606Ovaries pCMVSport 3.0 H0685 Adenocarcinoma of Ovary, Human Cell LineAdenocarcinoma of Ovary, pCMVSport 3.0 # OVCAR-3 Human Cell Line, #OVCAR- H0686 Adenocarcinoma of Ovary, Human Cell Line Adenocarcinoma ofOvary, pCMVSport 3.0 Human Cell Line, # SW-626 H0687 Human normalovary(#9610G215) Human normal Ovary pCMVSport 3.0 ovary(#9610G215) H0688Human Ovarian Cancer(#9807G017) Human Ovarian pCMVSport 3.0cancer(#9807G017), mRNA from Maura Ru H0689 Ovarian Cancer OvarianCancer, #9806G019 pCMVSport 3.0 H0690 Ovarian Cancer, # 9702G001 OvarianCancer, #9702G001 pCMVSport 3.0 H0691 Normal Ovary, #9710G208 normalovary, #9710G208 pCMVSport 3.0 H0692 BLyS Receptor from ExpressionCloning B Cell Lymphoma B Cell pCMVSport 3.0 H0693 Normal Prostate#ODQ3958EN Normal Prostate Tissue # pCMVSport 3.0 ODQ3958EN H0694Prostate gland adenocarcinoma Prostate gland, prostate gland pCMVSport3.0 adenocarcinoma, mod/diff, gleason H0695 mononucleocytes from patientmononucleocytes from pCMVSport 3.0 patient at Shady Grove Hospit N0006Human Fetal Brain Human Fetal Brain N0007 Human Hippocampus HumanHippocampus N0009 Human Hippocampus, prescreened Human Hippocampus N0011Human Brain Human Brain S0001 Brain frontal cortex Brain frontal cortexBrain Lambda ZAP II S0002 Monocyte activated Monocyte-activated bloodCell Line Uni-ZAP XR S0003 Human Osteoclastoma Osteoclastoma bonedisease Uni-ZAP XR S0004 Prostate Prostate BPH Prostate Lambda ZAP IIS0005 Heart Heart-left ventricle Heart pCDNA S0006 Neuroblastoma HumanNeural Blastoma disease pCDNA S0007 Early Stage Human Brain Human FetalBrain Uni-ZAP XR S0010 Human Amygdala Amygdala Uni-ZAP XR S0011STROMAL - OSTEOCLASTOMA Osteoclastoma bone disease Uni-ZAP XR S0013Prostate Prostate prostate Uni-ZAP XR S0014 Kidney Cortex Kidney cortexKidney Uni-ZAP XR S0015 Kidney medulla Kidney medulla Kidney Uni-ZAP XRS0016 Kidney Pyramids Kidney pyramids Kidney Uni-ZAP XR S0021 Wholebrain Whole brain Brain ZAP Express S0022 Human Osteoclastoma StromalCells - Osteoclastoma Stromal Cells Uni-ZAP XR unamplified S0024 HumanKidney Medulla - unamplified Human Kidney Medulla S0025 Human KidneyPyramids - unamplified Human Kidney Pyramids S0026 Stromal cell TF274stromal cell Bone marrow Cell Line Uni-ZAP XR S0027 Smooth muscle, serumtreated Smooth muscle Pulmanary Cell Line Uni-ZAP XR artery S0028 Smoothmuscle, control Smooth muscle Pulmanary Cell Line Uni-ZAP XR arteryS0029 brain stem Brain stem brain Uni-ZAP XR S0030 Brain pons Brain PonsBrain Uni-ZAP XR S0031 Spinal cord Spinal cord spinal cord Uni-ZAP XRS0032 Smooth muscle-ILb induced Smooth muscle Pulmanary Cell LineUni-ZAP XR artery S0035 Brain medulla oblongata Brain medulla oblongataBrain Uni-ZAP XR S0036 Human Substantia Nigra Human Substantia NigraUni-ZAP XR S0037 Smooth muscle, IL1b induced Smooth muscle PulmanaryCell Line Uni-ZAP XR artery S0038 Human Whole Brain #2 - Oligo dT >1.5Kb Human Whole Brain #2 ZAP Express S0039 Hypothalamus HypothalamusBrain Uni-ZAP XR S0040 Adipocytes Human Adipocytes from Uni-ZAP XROsteoclastoma S0041 Thalamus Human Thalamus Uni-ZAP XR S0042 TestesHuman Testes ZAP Express S0044 Prostate BPH prostate BPH Prostatedisease Uni-ZAP XR S0045 Endothelial cells-control Endothelial cellendothelial cell- Cell Line Uni-ZAP XR lung S0046 Endothelial-inducedEndothelial cell endothelial cell- Cell Line Uni-ZAP XR lung S0048 HumanHypothalamus, Alzheimer''s Human Hypothalamus, disease Uni-ZAP XRAlzheimer''s S0049 Human Brain, Striatum Human Brain, Striatum Uni-ZAPXR S0050 Human Frontal Cortex, Schizophrenia Human Frontal Cortex,disease Uni-ZAP XR Schizophrenia S0051 Human Hypothalmus, SchizophreniaHuman Hypothalamus, disease Uni-ZAP XR Schizophrenia S0052 neutrophilscontrol human neutrophils blood Cell Line Uni-ZAP XR S0053 NeutrophilsIL-1 and LPS induced human neutrophil induced blood Cell Line Uni-ZAP XRS0106 STRIATUM DEPRESSION BRAIN disease Uni-ZAP XR S0110 Brain AmygdalaDepression Brain disease Uni-ZAP XR S0112 Hypothalamus Brain Uni-ZAP XRS0114 Anergic T-cell Anergic T-cell Cell Line Uni-ZAP XR S0116 Bonemarrow Bone marrow Bone marrow Uni-ZAP XR S0118 Smooth muscle control 2Smooth muscle Pulmanary Cell Line Uni-ZAP XR artery S0122Osteoclastoma-normalized A Osteoclastoma bone disease pBluescript S0124Smooth muscle-edited A Smooth muscle Pulmanary Cell Line Uni-ZAP XRartery S0126 Osteoblasts Osteoblasts Knee Cell Line Uni-ZAP XR S0132Epithelial-TNFa and INF induced Airway Epithelial Uni-ZAP XR S0134Apoptotic T-cell apoptotic cells Cell Line Uni-ZAP XR S0136 PERM TF274stromal cell Bone marrow Cell Line Lambda ZAP II S0140 eosinophil-IL5induced eosinophil lung Cell Line Uni-ZAP XR S0142 Macrophage-oxLDLmacrophage-oxidized LDL blood Cell Line Uni-ZAP XR treated S0144Macrophage (GM-CSF treated) Macrophage (GM-CSF Uni-ZAP XR treated) S0146prostate-edited prostate BPH Prostate Uni-ZAP XR S0148 Normal ProstateProstate prostate Uni-ZAP XR S0150 LNCAP prostate cell line LNCAP CellLine Prostate Cell Line Uni-ZAP XR S0152 PC3 Prostate cell line PC3prostate cell line Uni-ZAP XR S0168 Prostate/LNCAP, subtraction I PC3prostate cell line pBluescript S0174 Prostate-BPH subtracted II HumanProstate BPH pBluescript S0176 Prostate, normal, subtraction I Prostateprostate Uni-ZAP XR S0180 Bone Marrow Stroma, TNF&LPS ind Bone MarrowStroma, TNF disease Uni-ZAP XR & LPS induced S0182 Human B Cell 8866Human B-Cell 8866 Uni-ZAP XR S0184 7TM Receptor enriched, lib II PBLS,7TM receptor Other enriched S0188 Prostate, BPH, Lib 2 Human ProstateBPH disease pSport1 S0190 Prostate BPH, Lib 2, subtracted Human ProstateBPH pSport1 S0192 Synovial Fibroblasts (control) Synovial FibroblastspSport1 S0194 Synovial hypoxia Synovial Fibroblasts pSport1 S0196Synovial IL-1/TNF stimulated Synovial Fibroblasts pSport1 S0202 7TM-pbddPBLS, 7TM receptor PCRII enriched S0206 Smooth Muscle- HASTE normalizedSmooth muscle Pulmanary Cell Line pBluescript artery S0208 Messangialcell, frac 1 Messangial cell pSport1 S0210 Messangial cell, frac 2Messangial cell pSport1 S0212 Bone Marrow Stromal Cell, untreated BoneMarrow Stromal pSport1 Cell, untreated S0214 Human Osteoclastoma,re-excision Osteoclastoma bone disease Uni-ZAP XR S0216 Neutrophils IL-1and LPS induced human neutrophil induced blood Cell Line Uni-ZAP XRS0218 Apoptotic T-cell, re-excision apoptotic cells Cell Line Uni-ZAP XRS0220 H. hypothalamus, frac A; re-excision Hypothalamus Brain ZAPExpress S0222 H. Frontal cortex, epileptic; re-excision H. Brain,Frontal Cortex, Brain disease Uni-ZAP XR Epileptic S0242 SynovialFibroblasts (Il1/TNF), subt Synovial Fibroblasts pSport1 S0250 HumanOsteoblasts II Human Osteoblasts Femur disease pCMVSport 2.0 S02527TM-PIMIX PBLS, 7TM receptor PCRII enriched S0256 7TM-PHMIX PBLS, 7TMreceptor PCRII enriched S0260 Spinal Cord, re-excision Spinal cordspinal cord Uni-ZAP XR S0264 PPMIX PPMIX (Human Pituitary) PituitaryPCRII S0266 PLMIX PLMIX (Human Lung) Lung PCRII S0268 PRMIX PRMIX (HumanProstate) prostate PCRII S0270 PTMIX PTMIX (Human Thymus) Thymus PCRIIS0276 Synovial hypoxia-RSF subtracted Synovial fobroblasts Synovialtissue pSport1 (rheumatoid) S0278 H Macrophage (GM-CSF treated), re-Macrophage (GM-CSF Uni-ZAP XR excision treated) S0280 Human AdiposeTissue, re-excision Human Adipose Tissue Uni-ZAP XR S0282 Brain FrontalCortex, re-excision Brain frontal cortex Brain Lambda ZAP II S0292Osteoarthritis (OA-4) Human Osteoarthritic Bone disease pSport1Cartilage S0294 Larynx tumor Larynx tumor Larynx, vocal disease pSport1cord S0296 Normal lung Normal lung Lung pSport1 S0298 Bone marrowstroma, treated Bone marrow Bone marrow pSport1 stroma, treatedSB S0300Frontal lobe, dementia; re-excision Frontal Lobe Brain Uni-ZAP XRdementia/Alzheimer''s S0306 Larynx normal #10 261-273 Larynx normalpSport1 S0308 Spleen/normal Spleen normal pSport1 S0310 Normal tracheaNormal trachea pSport1 S0312 Human osteoarthritic; fraction II Humanosteoarthritic disease pSport1 cartilage S0314 Human osteoarthritis;fraction I Human osteoarthritic disease pSport1 cartilage S0316 HumanNormal Cartilage, Fraction I Human Normal Cartilage pSport1 S0318 HumanNormal Cartilage Fraction II Human Normal Cartilage pSport1 S0320 HumanLarynx Larynx Epiglottis pSport1 S0322 Siebben Polyposis SiebbenPolyposis pSport1 S0324 Human Brain Brain Cerebellum pSport1 S0328Palate carcinoma Palate carcinoma Uvula disease pSport1 S0330 Palatenormal Palate normal Uvula pSport1 S0332 Pharynx carcinoma Pharynxcarcinoma Hypopharynx pSport1 S0334 Human Normal Cartilage Fraction IIIHuman Normal Cartilage pSport1 S0336 Human Normal Cartilage Fraction IVHuman Normal Cartilage pSport1 S0338 Human Osteoarthritic CartilageFraction III Human osteoarthritic disease pSport1 cartilage S0340 HumanOsteoarthritic Cartilage Fraction IV Human osteoarthritic diseasepSport1 cartilage S0342 Adipocytees; re-excision Human Adipocytes fromUni-ZAP XR Osteoclastoma S0344 Macrophage-oxLDL; re-excisionmacrophage-oxidized LDL blood Cell Line Uni-ZAP XR treated S0346 HumanAmygdala; re-excision Amygdala Uni-ZAP XR S0348 Cheek Carcinoma CheekCarcinoma disease pSport1 S0350 Pharynx Carcinoma Pharynx carcinomaHypopharynx disease pSport1 S0352 Larynx Carcinoma Larynx carcinomadisease pSport1 S0354 Colon Normal II Colon Normal Colon pSport1 S0356Colon Carcinoma Colon Carcinoma Colon disease pSport1 S0358 Colon NormalIII Colon Normal Colon pSport1 S0360 Colon Tumor II Colon Tumor Colondisease pSport1 S0362 Human Gastrocnemius Gastrocnemius muscle pSport1S0364 Human Quadriceps Quadriceps muscle pSport1 S0366 Human SoleusSoleus Muscle pSport1 S0368 Human Pancreatic Langerhans Islets ofLangerhans pSport1 S0370 Larynx carcinoma II Larynx carcinoma diseasepSport1 S0372 Larynx carcinoma III Larynx carcinoma disease pSport1S0374 Normal colon Normal colon pSport1 S0376 Colon Tumor Colon Tumordisease pSport1 S0378 Pancreas normal PCA4 No Pancreas Normal PCA4 NopSport1 S0380 Pancreas Tumor PCA4 Tu Pancreas Tumor PCA4 Tu diseasepSport1 S0382 Larynx carcinoma IV Larynx carcinoma disease pSport1 S0384Tongue carcinoma Tongue carcinoma disease pSport1 S0386 Human WholeBrain, re-excision Whole brain Brain ZAP Express S0388 HumanHypothalamus, schizophrenia, re- Human Hypothalamus, disease Uni-ZAP XRexcision Schizophrenia S0390 Smooth muscle, control; re-excision Smoothmuscle Pulmanary Cell Line Uni-ZAP XR artery S0392 Salivary GlandSalivary gland; normal pSport1 S0394 Stomach; normal Stomach; normalpSport1 S0396 Uterus; normal Uterus; normal pSport1 S0398 Testis; normalTestis; normal pSport1 S0400 Brain; normal Brain; normal pSport1 S0402Adrenal Gland, normal Adrenal gland; normal pSport1 S0404 Rectum normalRectum, normal pSport1 S0406 Rectum tumour Rectum tumour pSport1 S0408Colon, normal Colon, normal pSport1 S0410 Colon, tumour Colon, tumourpSport1 S0412 Temporal cortex-Alzheizmer; subtracted Temporal cortex,alzheimer disease Other S0414 Hippocampus, Alzheimer SubtractedHippocampus, Alzheimer Other Subtracted S0418 CHME Cell Line; treated 5hrs CHME Cell Line; treated pCMVSport 3.0 S0420 CHME Cell Line,untreated CHME Cell line, untreatetd pSport1 S0422 Mo7e Cell Line GM-CSFtreated (1 ng/ml) Mo7e Cell Line GM-CSF pCMVSport 3.0 treated (1 ng/ml)S0424 TF-1 Cell Line GM-CSF Treated TF-1 Cell Line GM-CSF pSport1Treated S0426 Monocyte activated; re-excision Monocyte-activated bloodCell Line Uni-ZAP XR S0428 Neutrophils control; re-excision humanneutrophils blood Cell Line Uni-ZAP XR S0430 Aryepiglottis NormalAryepiglottis Normal pSport1 S0432 Sinus piniformis Tumour Sinuspiniformis Tumour pSport1 S0434 Stomach Normal Stomach Normal diseasepSport1 S0436 Stomach Tumour Stomach Tumour disease pSport1 S0438 LiverNormal Met5No Liver Normal Met5No pSport1 S0440 Liver Tumour Met 5 TuLiver Tumour pSport1 S0442 Colon Normal Colon Normal pSport1 S0444 ColonTumor Colon Tumour disease pSport1 S0446 Tongue Tumour Tongue TumourpSport1 S0448 Larynx Normal Larynx Normal pSport1 S0450 Larynx TumourLarynx Tumour pSport1 S0452 Thymus Thymus pSport1 S0454 PlacentaPlacenta Placenta pSport1 S0456 Tongue Normal Tongue Normal pSport1S0458 Thyroid Normal (SDCA2 No) Thyroid normal pSport1 S0460 ThyroidTumour Thyroid Tumour pSport1 S0462 Thyroid Thyroiditis ThyroidThyroiditis pSport1 S0464 Larynx Normal Larynx Normal pSport1 S0466Larynx Tumor Larynx Tumor disease pSport1 S0468 Ea.hy.926 cell lineEa.hy.926 cell line pSport1 S0470 Adenocarcinoma PYFD disease pSport1S0472 Lung Mesothelium PYBT pSport1 S0474 Human blood plateletsPlatelets Blood platelets Other S0665 Human Amygdala; re-excissionAmygdala Uni-ZAP XR S3012 Smooth Muscle Serum Treated, Norm Smoothmuscle Pulmanary Cell Line pBluescript artery S3014 Smooth muscle, seruminduced, re-exc Smooth muscle Pulmanary Cell Line pBluescript arteryS6014 H. hypothalamus, frac A Hypothalamus Brain ZAP Express S6016 H.Frontal Cortex, Epileptic H. Brain, Frontal Cortex, Brain diseaseUni-ZAP XR Epileptic S6022 H. Adipose Tissue Human Adipose TissueUni-ZAP XR S6024 Alzheimers, spongy change Alzheimer''s/Spongy changeBrain disease Uni-ZAP XR S6026 Frontal Lobe, Dementia Frontal Lobe BrainUni-ZAP XR dementia/Alzheimer''s S6028 Human Manic Depression TissueHuman Manic depression Brain disease Uni-ZAP XR tissue T0001 Human BrownFat Brown Fat pBluescript SK− T0002 Activated T-cells Activated T-Cell,PBL Blood Cell Line pBluescript SK− fraction T0003 Human Fetal LungHuman Fetal Lung pBluescript SK− T0004 Human White Fat Human White FatpBluescript SK− T0006 Human Pineal Gland Human Pinneal Gland pBluescriptSK− T0007 Colon Epithelium Colon Epithelium pBluescriptISK− T0008Colorectal Tumor Colorectal Tumor disease pBluescript SK− T0010 HumanInfant Brain Human Infant Brain Other T0023 Human Pancreatic CarcinomaHuman Pancreatic disease pBluescript SK− Carcinoma T0039 HSA 172 CellsHuman HSA 172 cell line pBluescript SK− T0040 HSC172 cells SA172 CellspBluescript SK− T0041 Jurkat T-cell G1 phase Jurkat T-cell pBluescriptSK− T0042 Jurkat T-Cell, S phase Jurkat T-Cell Line pBluescript SK−T0047 T lymphocytes >70 T lymphocytes >70 pBluescript SK− T0048 HumanAortic Endothelium Human Aortic Endothilium pBluescript SK− T0049 Aortaendothelial cells + TNF-a Aorta endothelial cells pBluescript SK− T0060Human White Adipose Human White Fat pBluescript SK− T0067 Human ThyroidHuman Thyroid pBluescript SK− T0068 Normal Ovary, Premenopausal NormalOvary, pBluescript SK− Premenopausal T0069 Human Uterus, normal HumanUterus, normal pBluescript SK− T0070 Human Adrenal Gland Human AdrenalGland pBluescript SK− T0071 Human Bone Marrow Human Bone MarrowpBluescript SK− T0078 Human Liver, normal adult Human Liver, normalAdult pBluescript SK− T0079 Human Kidney, normal Adult Human Kidney,normal pBluescript SK− Adult T0082 Human Adult Retina Human Adult RetinapBluescript SK− T0090 Liver, normal pBluescript SK− T0091 Liver,hepatocellular carcinoma pBluescript SK− T0104 HCC cell line metastisisto liver pBluescript SK− T0109 Human (HCC) cell line liver (mouse)pBluescript SK− metastasis, remake T0110 Human colon carcinoma (HCC)cell line, pBluescript SK− remake T0112 Human (Caco-2) cell line,adenocarcinoma, pBluescript SK− colon T0114 Human (Caco-2) cell line,adenocarcinoma, pBluescript SK− colon, remake T0115 Human ColonCarcinoma (HCC) cell line pBluescript SK− L0002 Atrium cDNA libraryHuman heart L0004 ClonTech HL 1065a L0005 Clontech human aorta polyA+mRNA (#6572) L0009 EST from 8p21.3-p22 L0012 HDMEC cDNA library L0015Human L0021 Human adult (K. Okubo) L0022 Human adult lung 3'' directedMboI cDNA L0024 Human brain ARSanders L0032 Human chromosome 12p cDNAsL0034 Human chromosome 14 L0038 Human chromosome 6 L0040 Human colonmucosa L0041 Human epidermal keratinocyte L0045 Human keratinocytedifferential display (B. Lin) L0051 Human mRNA (Tripodis and Ragoussis)L0052 Human normalized K562-cDNA L0055 Human promyclocyte L0060 Humanthymus NSTH II L0065 Liver HepG2 cell line. L0070 Selected chromosome 21cDNA library L0096 Subtracted human retina L0097 Subtracted humanretinal pigment epithelium (RPE) L0103 DKFZphamy1 amygdala L0105 Humanaorta polyA+ (TFujiwara) aorta L0109 Human brain cDNA brain L0118 Humanfetal brain S. Meier-Ewert brain L0126 Human fibroblast cDNA fibroblastL0138 Human normal gingiva normal gingiva L0141 Human pancreatic isletcell pancreatic islet L0142 Human placenta cDNA (TFujiwara) placentaL0143 Human placenta polyA+ (TFujiwara) placenta L0146 Human fovea cDNAretinal fovea L0149 DKFZphsnu1 subthalamic nucleus L0151 Human testis(C. De Smet) testis L0157 Human fetal brain (TFujiwara) brain L0158Human fetal brain QBoqin brain L0162 Human brain frontal cortex frontalcortex brain L0163 Human heart cDNA (YNakamura) heart L0171 Human lungadenocarcinoma A549 lung adenocarcinoma A549 L0175 Human retina cellline ARPE-19 retina ARPE-19 L0177 Human newborn melanocytes (T. Vogt)Clonetics Corp. (San Diego, CA) strain #68 and 2486 L0182 Human HeLa (Y.Wang) HeLa L0186 Human salivary gland cell line HSG salivary gland HSGL0194 Human pancreatic cancer cell line Patu 8988t pancreatic cancerPatu 8988t L0351 Infant brain, Bento Soares BA, M13-derived L0352Normalized infant brain, Bento Soares BA, M13-derived L0353 21qPlacenta, F. Tassone and K. Gardiner Bluescript L0355 P, Human foetalBrain Whole tissue Bluescript L0356 S, Human foetal Adrenals tissueBluescript L0361 Stratagene ovary (#937217) ovary Bluescript SK L0362Stratagene ovarian cancer (#937219) Bluescript SK− L0363 NCI_CGAP_GC2germ cell tumor Bluescript SK− L0364 NCI_CGAP_GC5 germ cell tumorBluescript SK− L0365 NCI_CGAP_Phe1 pheochromocytoma Bluescript SK− L0366Stratagene schizo brain S11 schizophrenic brain S-11 Bluescript SK−frontal lobe L0367 NCI_CGAP_Sch1 Schwannoma tumor Bluescript SK− L0368NCI_CGAP_SS1 synovial sarcoma Bluescript SK− L0369 NCI_CGAP_AA1 adrenaladenoma adrenal gland Bluescript SK− L0370 Johnston frontal cortexpooled frontal lobe brain Bluescript SK− L0371 NCI_CGAP_Br3 breast tumorbreast Bluescript SK− L0372 NCI_CGAP_Co12 colon tumor colon BluescriptSK− L0373 NCI_CGAP_Co11 tumor colon Bluescript SK− L0374 NCI_CGAP_Co2tumor colon Bluescript SK− L0375 NCI_CGAP_Kid6 kidney tumor kidneyBluescript SK− L0376 NCI_CGAP_Lar1 larynx larynx Bluescript SK− L0377NCI_CGAP_HN2 squamous cell carcinoma larynx Bluescript SK− from vocalcord L0378 NCI_CGAP_Lu1 lung tumor lung Bluescript SK− L0379NCI_CGAP_Lym3 lymphoma lymph node Bluescript SK− L0380 NCI_CGAP_HN1squamous cell carcinoma lymph node Bluescript SK− L0381 NCI_CGAP_HN4squamous cell carcinoma pharynx Bluescript SK− L0382 NCI_CGAP_Pr25epithelium (cell line) prostate Bluescript SK− L0383 NCI_CGAP_Pr24invasive tumor (cell line) prostate Bluescript SK− L0384 NCI_CGAP_Pr23prostate tumor prostate Bluescript SK− L0385 NCI_CGAP_Gas1 gastric tumorstomach Bluescript SK− L0386 NCI_CGAP_HN3 squamous cell carcinoma tongueBluescript SK− from base of tongue L0387 NCI_CGAP_GCB0 germinal centerB-cells tonsil Bluescript SK− L0388 NCI_CGAP_HN6 normal gingiva (cellline Bluescript SK− from immortalized kerati L0389 NCI_CGAP_HN5 normalgingiva (cell line Bluescript SK− from primary keratinocyt L0393 B,Human Liver tissue gt11 L0394 H, Human adult Brain Cortex tissue gt11L0404 b4HB3MA Cot109 + 103 + 85-Bio Lafmid A L0405 b4HB3MA Cot109 +103-Bio Lafmid A L0411 1-NIB Lafmid BA L0414 b4HB3MA Lafmid BA L0415b4HB3MA Cot8-HAP-Ft Lafmid BA L0416 b4HB3MA-Cot0.38-HAP-B Lafmid BAL0417 b4HB3MA-Cot0.38-HAP-Ft-6 Lafmid BA L0422 b4HB3MA-Cot12-HAP-BLafmid BA L0424 b4HB3MA-Cot14.5 Lafmid BA L0425 b4HB3MA-Cot18-Bio LafmidBA L0426 b4HB3MA-Cot51.5-HAP-Ft Lafmid BA L0427 b4HB3MA-FT20%-BiotinLafmid BA L0428 Cot1374Ft-4HB3MA Lafmid BA L0430 Cot250Ft-b4HB3MA LafmidBA L0434 Infant brain library of Dr. M. Soares lafmid BA L0435 Infantbrain, LLNL array of Dr. M. Soares lafmid BA 1NIB L0437 N-b4HB3MA-Cot109Lafmid BA L0438 normalized infant brain cDNA total brain brain lafmid BAL0439 Soares infant brain 1NIB whole brain Lafmid BA L0441 2HB3MK LafmidBK L0442 4HB3MK Lafmid BK L0443 b4HB3MK Lafmid BK L0446 N4HB3MK LafmidBK L0447 NHB3MK Lafmid BK L0448 3HFLSK20 Lafmid K L0451 N3HFLSK20 LafmidK L0453 BATM1 lambda gt10 L0454 Clontech adult human fat cell librarylambda gt10 HL1108A L0455 Human retina cDNA randomly primed retina eyelambda gt10 sublibrary L0456 Human retina cDNA Tsp509I-cleaved retinaeye lambda gt10 sublibrary L0457 multi-tissue normalized short-fragmentmulti-tissue pooled lambda gt10 L0459 Adult heart, Clontech Lambda gt11L0460 Adult heart, Lambda gt11 Lambda gt11 L0462 WATM1 lambda gt11 L0463fetal brain cDNA brain brain lambda gt11 L0465 TEST1, Human adult Testistissue lambda nm1149 L0468 HE6W lambda zap L0469 T, Human adultRhabdomyosarcoma Lambda Zap cell-line L0470 BL29 Burkitt''s lymphoma,Pascalis Sideras lambda ZAP 2 L0471 Human fetal heart, Lambda ZAPExpress Lambda ZAP Express L0475 KG1-a Lambda Zap Express cDNA libraryKG1-a Lambda Zap Express (Stratagene) L0476 Fetal brain, StratageneLambda ZAP II L0477 HPLA CCLee placenta Lambda ZAP II L0480 Stratagenecat#937212 (1992) Lambda ZAP, pBluescript SK(−) L0481 CD34+DIRECTIONALLambda ZAPII L0483 Human pancreatic islet Lambda ZAPII L0485 STRATAGENEHuman skeletal muscle skeletal muscle leg muscle Lambda ZAPII cDNAlibrary, cat. #936215. L0487 Human peripheral blood (Steve Elledge)whole peripheral blood Lambda-Yes L0492 Human Genomic pAMP L0493NCI_CGAP_Ov26 papillary serous carcinoma ovary pAMP1 L0497 NCI_CGAP_HSC4CD34+, CD38− from normal bone marrow pAMP1 bone marrow donor L0498NCI_CGAP_HSC3 CD34+, T negative, patient bone marrow pAMP1 with chronicmyelogenou L0499 NCI_CGAP_HSC2 stem cell 34+/38+ bone marrow pAMP1 L0500NCI_CGAP_Brn20 oligodendroglioma brain pAMP1 L0501 NCI_CGAP_Brn21oligodendroglioma brain pAMP1 L0502 NCI_CGAP_Br15 adenocarcinoma breastpAMP1 L0503 NCI_CGAP_Br17 adenocarcinoma breast pAMP1 L0504NCI_CGAP_Br13 breast carcinoma in situ breast pAMP1 L0505 NCI_CGAP_Br12invasive carcinoma breast pAMP1 L0506 NCI_CGAP_Br16 lobullar carcinomain situ breast pAMP1 L0507 NCI_CGAP_Br14 normal epithelium breast pAMP1L0508 NCI_CGAP_Lu25 bronchioalveolar carcinoma lung pAMP1 L0509NCI_CGAP_Lu26 invasive adenocarcinoma lung pAMP1 L0510 NCI_CGAP_Ov33borderline ovarian carcinoma ovary pAMP1 L0511 NCI_CGAP_Ov34 borderlineovarian carcinoma ovary pAMP1 L0512 NCI_CGAP_Ov36 borderline ovariancarcinoma ovary pAMP1 L0513 NCI_CGAP_Ov37 early stage papillary serousovary pAMP1 carcinoma L0514 NCI_CGAP_Ov31 papillary serous carcinomaovary pAMP1 L0515 NCI_CGAP_Ov32 papillary serous carcinoma ovary pAMP1L0516 Chromosome 19p12-p13.1 exon pAMP10 L0517 NCI_CGAP_Pr1 pAMP10 L0518NCI_CGAP_Pr2 pAMP10 L0519 NCI_CGAP_Pr3 pAMP10 L0520 NCI_CGAP_Alv1alveolar rhabdomyosarcoma pAMP10 L0521 NCI_CGAP_Ew1 Ewing''s sarcomapAMP10 L0522 NCI_CGAP_Kid1 kidney pAMP10 L0523 NCI_CGAP_Lip2 liposarcomapAMP10 L0524 NCI_CGAP_Li1 liver pAMP10 L0525 NCI_CGAP_Li2 liver pAMP10L0526 NCI_CGAP_Pr12 metastatic prostate bone pAMP10 lesion L0527NCI_CGAP_Ov2 ovary pAMP10 L0528 NCI_CGAP_Pr5 prostate pAMP10 L0529NCI_CGAP_Pr6 prostate pAMP10 L0530 NCI_CGAP_Pr8 prostate pAMP10 L0531NCI_CGAP_Pr20 prostate metastasis, liver pAMP10 L0532 NCI_CGAP_Thy1thyroid pAMP10 L0533 NCI_CGAP_HSC1 stem cells bone marrow pAMP10 L0534Chromosome 7 Fetal Brain cDNA Library brain brain pAMP10 L0535NCI_CGAP_Br5 infiltrating ductal carcinoma breast pAMP10 L0536NCI_CGAP_Br4 normal ductal tissue breast pAMP10 L0537 NCI_CGAP_Ov6normal cortical stroma ovary pAMP10 L0539 Chromosome 7 Placental cDNALibrary placenta pAMP10 L0540 NCI_CGAP_Pr10 invasive prostate tumorprostate pAMP10 L0541 NCI_CGAP_Pr7 low-grade prostatic neoplasiaprostate pAMP10 L0542 NCI_CGAP_Pr11 normal prostatic epithelial prostatepAMP10 cells L0543 NCI_CGAP_Pr9 normal prostatic epithelial prostatepAMP10 cells L0544 NCI_CGAP_Pr4 prostatic intraepithelial prostatepAMP10 neoplasia —high grade L0545 NCI_CGAP_Pr4.1 prostaticintraepithelial prostate pAMP10 neoplasia —high grade L0546NCI_CGAP_Pr18 stroma prostate pAMP10 L0547 NCI_CGAP_Pr16 tumor prostatepAMP10 L0548 Chromosome 7 Thymus cDNA Library thymus thymus pAMP10 L0549NCI_CGAP_HN10 carcinoma in situ from pAMP10 retromolar trigone L0550NCI_CGAP_HN9 normal squamous epithelium pAMP10 from retromolar trigoneL0551 NCI_CGAP_HN7 normal squamous pAMP10 epithelium, floor of mouthL0552 NCI_CGAP_HN8 well-differentiated invasive pAMP10 carcinoma, floorof m L0553 NCI_CGAP_Co22 colonic adenocarcinoma colon pAMP10 L0554NCI_CGAP_Li8 liver pAMP10 L0555 NCI_CGAP_Lu34 large cell carcinoma lungpAMP10 L0556 NCI_CGAP_Lu34.1 large cell carcinoma lung pAMP10 L0558NCI_CGAP_Ov40 endometrioid ovarian ovary pAMP10 metastasis L0559NCI_CGAP_Ov39 papillary serous ovarian ovary pAMP10 metastasis L0560NCI_CGAP_HN12 moderate to poorly tongue pAMP10 differentiated invasivecarcino L0561 NCI_CGAP_HN11 normal squamous epithelium tongue pAMP10L0562 Chromosome 7 HeLa cDNA Library HeLa cell pAMP10 line; ATCC L0563Human Bone Marrow Stromal Fibroblast bone marrow pBluescript L0564 Jiabone marrow stroma bone marrow stroma pBluescript L0565 Normal HumanTrabecular Bone Cells Bone Hip pBluescript L0579 Human fetal brainQBoqin2 cerebrum and cerebellum pBluescript SK L0581 Stratagene liver(#937224) liver pBluescript SK L0583 Stratagene cDNA library Humanfibroblast, pBluescript SK(+) cat#937212 L0584 Stratagene cDNA libraryHuman heart, pBluescript SK(+) cat#936208 L0586 HTCDLI pBluescript SK(−)L0587 Stratagene colon HT29 (#937221) pBluescript SK− L0588 Stratageneendothelial cell 937223 pBluescript SK− L0589 Stratagene fetal retina937202 pBluescript SK− L0590 Stratagene fibroblast (#937212) pBluescriptSK− L0591 Stratagene HeLa cell s3 937216 pBluescript SK− L0592Stratagene hNT neuron (#937233) pBluescript SK− L0593 Stratageneneuroepithelium (#937231) pBluescript SK− L0594 Stratageneneuroepithelium NT2RAMI pBluescript SK− 937234 L0595 Stratagene NT2neuronal precursor 937230 neuroepithelial cells brain pBluescript SK−L0596 Stratagene colon (#937204) colon pBluescript SK− L0597 Stratagenecorneal stroma (#937222) cornea pBluescript SK− L0598 Morton FetalCochlea cochlea ear pBluescript SK− L0599 Stratagene lung (#937210) lungpBluescript SK− L0600 Weizmann Olfactory Epithelium olfactory epitheliumnose pBluescript SK− L0601 Stratagene pancreas (#937208) pancreaspBluescript SK− L0602 Pancreatic Islet pancreatic islet pancreaspBluescript SK− L0603 Stratagene placenta (#937225) placenta pBluescriptSK− L0604 Stratagene muscle 937209 muscle skeletal muscle pBluescriptSK− L0605 Stratagene fetal spleen (#937205) fetal spleen spleenpBluescript SK− L0606 NCI_CGAP_Lym5 follicular lymphoma lymph nodepBluescript SK− L0607 NCI_CGAP_Lym6 mantle cell lymphoma lymph nodepBluescript SK− L0608 Stratagene lung carcinoma 937218 lung carcinomalung NCI-H69 pBluescript SK− L0609 Schiller astrocytoma astrocytomabrain pBluescript SK− (Stratagene) L0611 Schiller meningioma meningiomabrain pBluescript SK− (Stratagene) L0612 Schiller oligodendrogliomaoligodendroglioma brain pBluescript SK− (Stratagene) L0615 22 week oldhuman fetal liver cDNA library pBluescriptII SK(−) L0617 Chromosome 22exon pBluescriptIIKS+ L0619 Chromosome 9 exon II pBluescriptIIKS+ L0622HM1 pcDNAII (Invitrogen) L0623 HM3 pectoral muscle (after pcDNAIImastectomy) (Invitrogen) L0625 NCI_CGAP_AR1 bulk alveolar tumorpCMV-SPORT2 L0626 NCI_CGAP_GC1 bulk germ cell seminoma pCMV-SPORT2 L0627NCI_CGAP_Col bulk tumor colon pCMV-SPORT2 L0628 NCI_CGAP_Ov1 ovary bulktumor ovary pCMV-SPORT2 L0629 NCI_CGAP_Mel3 metastatic melanoma to bowel(skin pCMV-SPORT4 bowel primary) L0630 NCI_CGAP_CNS1 substantia nigrabrain pCMV-SPORT4 L0631 NCI_CGAP_Br7 breast pCMV-SPORT4 L0632NCI_CGAP_Li5 hepatic adenoma liver pCMV-SPORT4 L0633 NCI_CGAP_Lu6 smallcell carcinoma lung pCMV-SPORT4 L0634 NCI_CGAP_Ov8 serous adenocarcinomaovary pCMV-SPORT4 L0635 NCI_CGAP_PNS1 dorsal root ganglion peripheralpCMV-SPORT4 nervous system L0636 NCI_CGAP_Pit1 four pooled pituitarybrain pCMV-SPORT6 adenomas L0637 NCI_CGAP_Brn53 three pooled meningiomasbrain pCMV-SPORT6 L0638 NCI_CGAP_Brn35 tumor, 5 pooled (see brainpCMV-SPORT6 description) L0639 NCI_CGAP_Brn52 tumor, 5 pooled (see brainpCMV-SPORT6 description) L0640 NCI_CGAP_Br18 four pooled high-gradebreast pCMV-SPORT6 tumors, including two prima L0641 NCI_CGAP_Co17juvenile granulosa tumor colon pCMV-SPORT6 L0642 NCI_CGAP_Co18moderately differentiated colon pCMV-SPORT6 adenocarcinoma L0643NCI_CGAP_Co19 moderately differentiated colon pCMV-SPORT6 adenocarcinomaL0644 NCI_CGAP_Co20 moderately differentiated colon pCMV-SPORT6adenocarcinoma L0645 NCI_CGAP_Co21 moderately differentiated colonpCMV-SPORT6 adenocarcinoma L0646 NCI_CGAP_Co14 moderately-differentiatedcolon pCMV-SPORT6 adenocarcinoma L0647 NCI_CGAP_Sar4 five pooledsarcomas, connective tissue pCMV-SPORT6 including myxoid liposarcomaL0648 NCI_CGAP_Eso2 squamous cell carcinoma esophagus pCMV-SPORT6 L0649NCI_CGAP_GU1 2 pooled high-grade genitourinary pCMV-SPORT6 transitionalcell tumors tract L0650 NCI_CGAP_Kid13 2 pooled Wilms” tumors, onekidney pCMV-SPORT6 primary and one metast L0651 NCI_CGAP_Kid8 renal celltumor kidney pCMV-SPORT6 L0652 NCI_CGAP_Lu27 four pooled poorly- lungpCMV-SPORT6 differentiated adenocarcinomas L0653 NCI_CGAP_Lu28 twopooled squamous cell lung pCMV-SPORT6 carcinomas L0654 NCI_CGAP_Lu31lung, cell line pCMV-SPORT6 L0655 NCI_CGAP_Lym12 lymphoma, follicularmixed lymph node pCMV-SPORT6 small and large cell L0656 NCI_CGAP_Ov38normal epithelium ovary pCMV-SPORT6 L0657 NCI_CGAP_Ov23 tumor, 5 pooled(see ovary pCMV-SPORT6 description) L0658 NCI_CGAP_Ov35 tumor, 5 pooled(see ovary pCMV-SPORT6 description) L0659 NCI_CGAP_Pan1 adenocarcinomapancreas pCMV-SPORT6 L0661 NCI_CGAP_Mel15 malignant melanoma, skinpCMV-SPORT6 metastatic to lymph node L0662 NCI_CGAP_Gas4 poorlydifferentiated stomach pCMV-SPORT6 adenocarcinoma with signet r L0663NCI_CGAP_Ut2 moderately-differentiated uterus pCMV-SPORT6 endometrialadenocarcino L0664 NCI_CGAP_Ut3 poorly-differentiated uterus pCMV-SPORT6endometrial adenocarcinoma, L0665 NCI_CGAP_Ut4 serous papillarycarcinoma, uterus pCMV-SPORT6 high grade, 2 pooled t L0666 NCI_CGAP_Ut1well-differentiated uterus pCMV-SPORT6 endometrial adenocarcinoma, 7L0667 NCI_CGAP_CML1 myeloid cells, 18 pooled whole blood pCMV-SPORT6 CMLcases, BCR/ABL rearra L0669 Human MCF7 cDNA subtracted with MDA- breastadenocarcinoma breast MCF7 pCR II [Invitrogen] MB-231 cDNA L0681 StanleyFrontal SN individual frontal lobe (see description) brain pCR2.1(Invitrogen) L0682 Stanley Frontal NB pool 2 frontal lobe (seedescription) brain pCR2.1-TOPO (Invitrogen) L0683 Stanley Frontal NSpool 2 frontal lobe (see description) brain pCR2.1-TOPO (Invitrogen)L0684 Stanley Frontal SB pool 1 frontal lobe (see description) brainpCR2.1-TOPO (Invitrogen) L0685 Stanley Frontal SN pool 1 frontal lobe(see description) brain pCR2.1-TOPO (Invitrogen) L0686 Stanley FrontalSN pool 2 frontal lobe (see description) brain pCR2.1-TOPO (Invitrogen)L0687 Stanley Hippocampus NB pool 1 hippocampus (see brain pCR2.1-TOPOdescription) (Invitrogen) L0688 Stanley Hippocampus SB pool 1hippocampus (see brain pCR2.1-TOPO description) (Invitrogen) L0689Stanley Hippocampus SN pool 1 hippocampus (see brain pCR2.1-TOPOdescription) (Invitrogen) L0695 Human Glialblastoma Cell Brain BT-325PCRII, Invitrogen L0697 Testis 1 PGEM 5zf(+) L0698 Testis 2 PGEM 5zf(+)L0700 Outward Alu-primed hncDNA library pGEM-3Z L0709 NIH_MGC_21choriocarcinoma placenta pOTB7 L0710 NIH_MGC_7 small cell carcinoma lungMGC3 pOTB7 L0716 PMA-induced HL60 cell subtraction library PMA- pSPORT 1induced HL60 human leukemic cell line L0717 Gessler Wilms tumor pSPORT1L0718 Testis 5 pSPORT1 L0719 human embryo cDNA library Whole embryopSPORT1 L0731 Soares_pregnant_uterus_NbHPU uterus pT7T3-Pac L0738 Humancolorectal cancer pT7T3D L0740 Soares melanocyte 2NbHM melanocyte pT7T3D(Pharmacia) with a modified polylinker L0741 Soares adult brainN2b4HB55Y brain pT7T3D (Pharmacia) with a modified polylinker L0742Soares adult brain N2b5HB55Y brain pT7T3D (Pharmacia) with a modifiedpolylinker L0743 Soares breast 2NbHBst breast pT7T3D (Pharmacia) with amodified polylinker L0744 Soares breast 3NbHBst breast pT7T3D(Pharmacia) with a modified polylinker L0745 Soares retina N2b4HR retinaeye pT7T3D (Pharmacia) with a modified polylinker L0746 Soares retinaN2b5HR retina eye pT7T3D (Pharmacia) with a modified polylinker L0747Soares_fetal_heart_NbHH19W heart pT7T3D (Pharmacia) with a modifiedpolylinker L0748 Soares fetal liver spleen 1NFLS Liver and Spleen pT7T3D(Pharmacia) with a modified polylinker L0749Soares_fetal_liver_spleen_1NFLS_S1 Liver and Spleen pT7T3D (Pharmacia)with a modified polylinker L0750 Soares_fetal_lung_NbHL19W lung pT7T3D(Pharmacia) with a modified polylinker L0751 Soares ovary tumor NbHOTovarian tumor ovary pT7T3D (Pharmacia) with a modified polylinker L0752Soares_parathyroid_tumor_NbHPA parathyroid tumor parathyroid pT7T3Dgland (Pharmacia) with a modified polylinker L0753Soares_pineal_gland_N3HPG pineal gland pT7T3D (Pharmacia) with amodified polylinker L0754 Soares placenta Nb2HP placenta pT7T3D(Pharmacia) with a modified polylinker L0755Soares_placenta_8to9weeks_2NbHP8to9W placenta pT7T3D (Pharmacia) with amodified polylinker L0756 Soares_multiple_sclerosis_2NbHMSP multiplesclerosis lesions pT7T3D (Pharmacia) with a modified polylinker V_TYPEL0757 Soares_senescent_fibroblasts_NbHSF senescent fibroblast pT7T3D(Pharmacia) with a modified polylinker V_TYPE L0758 Soares_testis_NHTpT7T3D-Pac (Pharmacia) with a modified polylinker L0759Soares_total_fetus_Nb2HF8_9w pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0760 Barstead aorta HPLRB3 aorta pT7T3D-Pac (Pharmacia) witha modified polylinker L0761 NCI_CGAP_CLL1 B-cell, chronic lymphoticpT7T3D-Pac leukemia (Pharmacia) with a modified polylinker L0762NCI_CGAP_Br1.1 breast pT7T3D-Pac (Pharmacia) with a modified polylinkerL0763 NCI_CGAP_Br2 breast pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0764 NCI_CGAP_Co3 colon pT7T3D-Pac (Pharmacia) with amodified polylinker L0765 NCI_CGAP_Co4 colon pT7T3D-Pac (Pharmacia) witha modified polylinker L0766 NCI_CGAP_GCB1 germinal center B cellpT7T3D-Pac (Pharmacia) with a modified polylinker L0767 NCI_CGAP_GC3pooled germ cell tumors pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0768 NCI_CGAP_GC4 pooled germ cell tumors pT7T3D-Pac(Pharmacia) with a modified polylinker L0769 NCI_CGAP_Brn25 anaplasticbrain pT7T3D-Pac oligodendroglioma (Pharmacia) with a modifiedpolylinker L0770 NCI_CGAP_Brn23 glioblastoma (pooled) brain pT7T3D-Pac(Pharmacia) with a modified polylinker L0771 NCI_CGAP_Co8 adenocarcinomacolon pT7T3D-Pac (Pharmacia) with a modified polylinker L0772NCI_CGAP_Co10 colon tumor RER+ colon pT7T3D-Pac (Pharmacia) with amodified polylinker L0773 NCI_CGAP_Co9 colon tumor RER+ colon pT7T3D-Pac(Pharmacia) with a modified polylinker L0774 NCI_CGAP_Kid3 kidneypT7T3D-Pac (Pharmacia) with a modified polylinker L0775 NCI_CGAP_Kid5 2pooled tumors (clear cell kidney pT7T3D-Pac type) (Pharmacia) with amodified polylinker L0776 NCI_CGAP_Lu5 carcinoid lung pT7T3D-Pac(Pharmacia) with a modified polylinker L0777 Soares_NhHMPu_S1 Pooledhuman melanocyte, mixed (see pT7T3D-Pac fetal heart, and pregnant below)(Pharmacia) with a modified polylinker L0778 Barstead pancreas HPLRB1pancreas pT7T3D-Pac (Pharmacia) with a modified polylinker L0779Soares_NFL_T_GBC_S1 pooled pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0780 Soares_NSF_F8_9W_OT_PA_P_S1 pooled pT7T3D-Pac(Pharmacia) with a modified polylinker L0782 NCI_CGAP_Pr21 normalprostate prostate pT7T3D-Pac (Pharmacia) with a modified polylinkerL0783 NCI_CGAP_Pr22 normal prostate prostate pT7T3D-Pac (Pharmacia) witha modified polylinker L0784 NCI_CGAP_Lei2 leiomyosarcoma soft tissuepT7T3D-Pac (Pharmacia) with a modified polylinker L0785 Barstead spleenHPLRB2 spleen pT7T3D-Pac (Pharmacia) with a modified polylinker L0786Soares_NbHFB whole brain pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0787 NCI_CGAP_Sub1 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0788 NCI_CGAP_Sub2 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0789 NCI_CGAP_Sub3 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0790 NCI_CGAP_Sub4 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0791 NCI_CGAP_Sub5 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0792 NCI_CGAP_Sub6 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0793 NCI_CGAP_Sub7 pT7T3D-Pac (Pharmacia) with a modifiedpolylinker L0794 NCI_CGAP_GC6 pooled germ cell tumors pT7T3D-Pac(Pharmacia) with a modified polylinker L0796 NCI_CGAP_Brn50medulloblastoma brain pT7T3D-Pac (Pharmacia) with a modified polylinkerL0800 NCI_CGAP_Co16 colon tumor, RER+ colon pT7T3D-Pac (Pharmacia) witha modified polylinker L0803 NCI_CGAP_Kid11 kidney pT7T3D-Pac (Pharmacia)with a modified polylinker L0804 NCI_CGAP_Kid12 2 pooled tumors (clearcell kidney pT7T3D-Pac type) (Pharmacia) with a modified polylinkerL0805 NCI_CGAP_Lu24 carcinoid lung pT7T3D-Pac (Pharmacia) with amodified polylinker L0806 NCI_CGAP_Lu19 squamous cell carcinoma, lungpT7T3D-Pac poorly differentiated (4 (Pharmacia) with a modifiedpolylinker L0807 NCI_CGAP_Ov18 fibrotheoma ovary pT7T3D-Pac (Pharmacia)with a modified polylinker L0808 Barstead prostate BPH HPLRB4 1 prostatepT7T3D-Pac (Pharmacia) with a modified polylinker L0809 NCI_CGAP_Pr28prostate pT7T3D-Pac (Pharmacia) with a modified polylinker L0811 BATM2PTZ18 L0988 BT0387 breast puc18 L1430 CT0225 colon puc18 L1562 CN0027colon_normal puc18 L1819 HT0268 head_neck puc18 L2138 ST0186 stomachpuc18 L2245 NEM subtracted human fetal kidney cDNA pUEX1 L2250 Humancerebral cortex cerebral cortex L2251 Human fetal lung Fetal lung L2252Human placenta placenta L2255 GLC corresponding non cancerouspBluescript sk(−) liver tissue L2257 NIH_MGC_65 adenocarcinoma colonpCMV-SPORT6 L2258 NIH_MGC_67 retinoblastoma eye pCMV-SPORT6 L2259NIH_MGC_68 large cell carcinoma lung pCMV-SPORT6 L2260 NIH_MGC_69 largecell carcinoma, lung pCMV-SPORT6 undifferentiated L2261 NIH_MGC_70epithelioid carcinoma pancreas pCMV-SPORT6 L2262 NIH_MGC_72 melanoticmelanoma skin pCMV-SPORT6 L2263 NIH_MGC_66 adenocarcinoma ovarypCMV-SPORT6 L2264 NIH_MGC_71 leiomyosarcoma uterus pCMV-SPORT6 L2265NIH_MGC_39 adenocarcinoma pancreas pOTB7 L2269 NCI_CGAP_Thy11 follicularcarcinoma thyroid pAMP10 L2270 Lupski_dorsal_root_ganglion dorsal rootganglia pCMV-SPORT6 (Life Technologies) L2285 BT0723 breast puc18 L2289BT0757 breast puc18 L2293 BT0762 breast puc18 L2300 BT0789 breast puc18L2323 CT0406 colon puc18 L2336 CT0428 colon puc18 L2352 UT0001uterus_tumor puc18 L2357 UT0021 uterus_tumor puc18 L2359 UT0023uterus_tumor puc18 L2368 UT0041 uterus_tumor puc18 L2380 NN0068nervous_normal puc18 L2381 NN0070 nervous_normal puc18 L2402 NN0118nervous_normal puc18 L2412 NN0136 nervous_normal puc18 L2439 NN1022nervous_normal puc18 L2482 HT0497 head_neck puc18 L2486 HT0527 head_neckpuc18 L2487 HT0542 head_neck puc18 L2491 HT0559 head_neck puc18 L2497HT0618 head_neck puc18 L2499 HT0622 head_neck puc18 L2504 HT0636head_neck puc18 L2519 HT0698 head_neck puc18 L2528 HT0713 head_neckpuc18 L2543 HT0734 head_neck puc18 L2551 HT0744 head_neck puc18 L2630HT0865 head_neck puc18 L2635 HT0875 head_neck puc18 L2647 HT0894head_neck puc18 L2652 NIH_MGC_57 glioblastoma brain pDNR-LIB (Clontech)L2653 NIH_MGC_58 hypernephroma kidney pDNR-LIB (Clontech) L2654NIH_MGC_9 adenocarcinoma cell line ovary pOTB7 L2655 NIH_MGC_55 fromacute myelogenous bone marrow pDNR-LIB leukemia (Clontech) L2657NIH_MGC_54 from chronic myelogenous bone marrow pDNR-LIB leukemia(Clontech) L2669 NT0022 nervous_tumor puc18 L2670 NT0023 nervous_tumorpuc18 L2673 NT0028 nervous_tumor puc18 L2675 NT0033 nervous_tumor puc18L2706 NT0102 nervous_tumor puc18 L2744 FT0004 prostate_tumor puc18 L2758FT0027 prostate_tumor puc18 L2759 FT0028 prostate_tumor puc18 L2767FT0044 prostate_tumor puc18 L2771 FT0050 prostate_tumor puc18 L2777FT0056 prostate_tumor puc18 L2791 FT0077 prostate_tumor puc18 L2800FT0097 prostate_tumor puc18 L2842 UM0009 uterus puc18 L2877 AN0027amnion_normal puc18 L2879 AN0032 amnion_normal puc18 L2903 BN0039breast_normal puc18 L2904 BN0042 breast_normal puc18 L2906 BN0047breast_normal puc18 L2909 BN0067 breast_normal puc18 L2910 BN0070breast_normal puc18 L2915 BN0098 breast_normal puc18 L2985 BN0257breast_normal puc18 L2991 BN0264 breast_normal puc18 L2999 BN0273breast_normal puc18 L3001 BN0275 breast_normal puc18 L3012 BN0296breast_normal puc18 L3019 BN0303 breast_normal puc18 L3092 ET0023lung_tumor puc18 L3109 ET0046 lung_tumor puc18 L3117 ET0068 lung_tumorpuc18 L3119 ET0072 lung_tumor puc18 L3180 MT0101 marrow puc18 L3181MT0107 marrow puc18 L3210 OT0067 ovary puc18 L3215 OT0083 ovary puc18L3271 FN0094 prostate_normal puc18 L3278 FN0104 prostate_normal puc18L3280 FN0106 prostate_normal puc18 L3311 FN0180 prostate_normal puc18L3327 SN0024 stomach_normal puc18 L3357 TN0034 testis_normal puc18 L3372TN0068 testis_normal puc18 L3378 TN0080 testis_normal puc18 L3385 Homosapiens HeLa HeLa L3387 GKB hepatocellular carcinoma pBluescript sk(−)L3388 GKC hepatocellular carcinoma pBluescript sk(−) L3391 NIH_MGC_53carcinoma, cell line bladder pDNR-LIB (Clontech) L3450 CT0508 colonpuc18 L3485 GN0070 placenta_normal puc18 L3499 HT0617 head_neck puc18L3503 HT0870 head_neck puc18 L3516 HT0913 head_neck puc18 L3560 TN0023testis_normal puc18 L3563 TN0037 testis_normal puc18 L3566 TN0046testis_normal puc18 L3576 TN0086 testis_normal puc18 L3585 TN0119testis_normal puc18 L3592 TN0129 testis_normal puc18 L3630 UT0071uterus_tumor puc18 L3632 UT0074 uterus_tumor puc18 L3642 ADA Adrenalgland pBluescript sk(−) L3643 ADB Adrenal gland pBluescript sk(−) L3644ADC Adrenal gland pBluescript sk(−) L3645 Cu adrenal cortico adenoma forpBluescript sk(−) Cushing''s syndrome L3646 DCA pTriplEx2 L3647 HumanHO-1 melanoma cells L3649 DCB pTriplEx2 L3651 FHTA hypothalamuspTriplEx2 L3652 FHTB hypothalamus pTriplEx2 L3653 HTB HypothalamuspBluescript sk(−) L3655 HTC Hypothalamus pBluescript sk(−) L3657 HTFHypothalamus pBluescript sk(−) L3658 cdA pheochromocytoma pTriplEx2L3659 CB cord blood pBluescript L3660 NP1 pituitary pBluescript sk(−)L3661 NPA pituitary pBluescript sk(−) L3663 NIH_MGC_60 adenocarcinomaprostate pDNR-LIB (Clontech) L3665 NIH_MGC_75 kidney pDNR-LIB (Clontech)L3709 CT0515 colon puc18 L3726 GN0038 placenta_normal puc18 L3729 GN0079placenta_normal puc18 L3750 HT0945 head_neck puc18 L3783 TN0136testis_normal puc18 L3796 UT0042 uterus_tumor puc18 L3807 UT0077uterus_tumor puc18 L3811 NPC pituitary pBluescript sk(−) L3812 NPDpituitary pBluescript sk(−) L3813 TP pituitary tumor pTriplEx2 L3814 BMBone marrow pTriplEx2 L3815 MDS Bone marrow pTriplEx2 L3816 HEMBA1 wholeembryo, mainly head pME18SFL3 L3817 HEMBB1 whole embryo, mainly bodypME18SFL3 L3818 MAMMA1 mammary gland pME18SFL3 L3820 NIH_MGC_46leiomyosarcoma cell line uterus pOTB7 L3821 NIH_MGC_48 primary B-cellsfrom tonsils B-cells pOTB7 (cell line) L3822 NIH_MGC_59 mucoepidermoidcarcinoma lung pDNR-LIB (Clontech) L3823 NT2RM1 NT2 pUC19FL3 L3824NT2RM2 NT2 pME18SFL3 L3825 NT2RM4 NT2 pME18SFL3 L3826 NT2RP1 NT2pUC19FL3 L3827 NT2RP2 NT2 pME18SFL3 L3828 NT2RP3 NT2 pME18SFL3 L3829NT2RP4 NT2 pME18SFL3 L3831 OVARC1 ovary, tumor tissue pME18SFL3 L3832PLACE1 placenta pME18SFL3 L3833 PLACE2 placenta pME18SFL3 L3834 PLACE3placenta pME18SFL3 L3837 THYRO1 thyroid gland pME18SFL3 L3872NCI_CGAP_Skn1 skin, normal, 4 pCMV-SPORT6 pooled sa L3904 NCI_CGAP_Brn64glioblastoma with EGFR brain pCMV-SPORT6 amplification L3905NCI_CGAP_Brn67 anaplastic brain pCMV-SPORT6 oligodendroglioma with1p/19q loss L4497 NCI_CGAP_Br22 invasive ductal carcinoma, 3 breastpCMV-SPORT6 pooled samples L4500 NCI_CGAP_HN16 moderate to poorly mouthpAMP10 differentiated invasive carcino L4501 NCI_CGAP_Sub8 pT7T3D-Pac(Pharmacia) with a modified polylinker L4507 NCI_CGAP_Thy6 normalepithelium thyroid pAMP10 L4508 NCI_CGAP_Thy8 normal epithelium thyroidpAMP10 L4537 NCI_CGAP_Thy7 follicular adenoma (benign thyroid pAMP10lesion) L4556 NCI_CGAP_HN13 squamous cell carcinoma tongue pCMV-SPORT6L4557 NCI_CGAP_Adr1 neuroblastoma adrenal gland pCMV-SPORT6 L4558NCI_CGAP_Pan3 pancreas pCMV-SPORT6 L4559 NCI_CGAP_Thy3 follicularcarcinoma thyroid pCMV-SPORT6 L4560 NCI_CGAP_Ut7 tumor uteruspCMV-SPORT6 L4669 NCI_CGAP_Ov41 serous papillary tumor ovary pCMV-SPORT6L4747 NCI_CGAP_Brn41 oligodendroglioma brain pT7T3D-Pac (Pharmacia) witha modified polylinker L4753 NCI_CGAP_HN15 leukoplakia of the buccalmouth pAMP10 mucosa L4775 NCI_CGAP_Thy12 papillary carcinoma thyroidpAMP10 L5286 NCI_CGAP_Thy10 medullary carcinoma thyroid pAMP10 L5564NCI_CGAP_HN20 normal pAMP1 head/neck tissue L5565 NCI_CGAP_Brn66glioblastoma with probably brain pCMV-SPORT6 TP53 mutation and withoL5566 NCI_CGAP_Brn70 anaplastic brain pCMV- oligodendrogliomaSPORT6.ccdb L5568 NCI_CGAP_HN21 nasopharyngeal carcinoma head/neck pAMP1L5569 NCI_CGAP_HN17 normal epithetlium nasopharynx pAMP10 L5572NCI_CGAP_Co27 adenocarcinoma (mucinous colon pAMP1 component) L5574NCI_CGAP_HN19 normal epithetlium nasopharynx pAMP10 L5575 NCI_CGAP_Brn65glioblastoma without EGFR brain pCMV-SPORT6 amplification L5622NCI_CGAP_Skn3 skin pCMV-SPORT6 L5623 NCI_CGAP_Skn4 squamous cellcarcinoma skin pCMV-SPORT6Description of Table 5

Table 5 provides a key to the OMIM reference identification numbersdisclosed in Table 1B. 1, column 9. OMIM reference identificationnumbers (Column 1) were derived from Online Mendelian Inheritance in Man(Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institutefor Genetic Medicine, Johns Hopkins University (Baltimore, Md.) andNational Center for Biotechnology Information, National Library ofMedicine, (Bethesda, Md.) 2000. World Wide Web URL:http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseasesassociated with the cytologic band disclosed in Table 1B.1, column 8, asdetermined using the Morbid Map database. TABLE 5 OMIM ReferenceDescription 100678 ACAT2 deficiency 100690 Myasthenic syndrome,slow-channel congenital, 601462 100710 Myasthenic syndrome, slow-channelcongenital, 601462 100730 Myasthenia gravis, neonatal transient 101000Meningioma, NF2-related, sporadic Schwannoma, sporadic 101000Neurofibromatosis, type 2 101000 Neurolemmomatosis 101000 Malignantmesothelioma, sporadic 102200 Somatotrophinoma 102540 Cardiomyopathy,idiopathic dilated 102578 Leukemia, acute promyelocytic, PML/RARA type102700 Severe combined immunodeficiency due to ADA deficiency 102700Hemolytic anemia due to ADA excess 102770 Myoadenylate deaminasedeficiency 102772 [AMP deaminase deficiency, erythrocytic] 103000Hemolytic anemia due to adenylate kinase deficiency 103050 Autism,succinylpurinemic 103050 Adenylosuccinase deficiency 103581 Albrighthereditary osteodystrophy-2 103600 [Dysalbuminemic hyperthyroxinemia]103600 [Dysalbuminemic hyperzincemia], 194470 103600 Analbuminemia103720 Alcoholism, susceptibility to 103850 Aldolase A deficiency 103950Emphysema due to alpha-2-macroglobulin deficiency 104150 [AFPdeficiency, congenital] 104150 [Hereditary persistence ofalpha-fetoprotein] 104311 Alzheimer disease-3 104500 Amelogenesisimperfecta-2, hypoplastic local type 104770 Amyloidosis, secondary,susceptibility to 105580 Anal canal carcinoma 105600 Dyserythropoieticanemia, congenital, type III 106100 Angioedema, hereditary 106150Hypertension, essential, susceptibility to 106150 Preeclampsia,susceptibility to 106165 Hypertension, essential, 145500 106180Myocardial infarction, susceptibility to 106210 Peters anomaly 106210Cataract, congenital, with late-onset corneal dystrophy 106210 Fovealhypoplasia, isolated, 136520 106210 Aniridia 106300 Ankylosingspondylitis 107250 Anterior segment mesenchymal dysgenesis 107271 CD59deficiency 107300 Antithrombin III deficiency 107470 Atypicalmycobacterial infection, familial disseminated, 209950 107470 BCGinfection, generalized familial 107470 Tuberculosis, susceptibility to107670 Apolipoprotein A-II deficiency 107680 ApoA-I and apoC-IIIdeficiency, combined 107680 Corneal clouding, autosomal recessive 107680Amyloidosis, 3 or more types 107680 Hypertriglyceridemia, one form107680 Hypoalphalipoproteinemia 107720 Hypertriglyceridemia 107741Hyperlipoproteinemia, type III 107777 Diabetes insipidus, nephrogenic,autosomal recessive, 222000 107970 Arrhythmogenic right ventriculardysplasia-1 108120 Distal arthrogryposis-1 108725 Atherosclerosis,susceptibility to 108730 Brody myopathy, 601003 108800 Atrial septaldefect, secundum type 108962 Hypertension, salt-resistant 108985Atrophia areata 109150 Machado-Joseph disease 109270 Renal tubularacidosis, distal, 179800 109270 Spherocytosis, hereditary 109270[Acanthocytosis, one form] 109270 [Elliptocytosis, Malaysian-Melanesiantype] 109270 Hemolytic anemia due to band 3 defect 109565 Lymphoma,B-cell 109565 Lymphoma, diffuse large cell 109690 Asthma, nocturnal,susceptibility to 109690 Obesity, susceptibility to 109700Hemodialysis-related amyloidosis 110100 Blepharophimosis, epicanthusinversus, and ptosis, type 1 110700 Vivax malaria, susceptibility to112250 Bone dysplasia with medullary fibrosarcoma 112262 Fibrodysplasiaossificans progressiva, 135100 112410 Hypertension with brachydactyly113721 Breast cancer 113811 Epidermolysis bullosa, generalized atrophicbenign, 226650 113900 Heart block, progressive familial, type I 114130Osteoporosis 114208 Malignant hyperthermia susceptibility 5, 601887114208 Hypokalemic periodic paralysis, 170400 114240 Muscular dystrophy,limb-girdle, type 2A, 253600 114290 Campomelic dysplasia with autosomalsex reversal 114350 Leukemia, acute myeloid 114400 Lynch cancer familysyndrome II 114550 Hepatocellular carcinoma 114835 Monocytecarboxyesterase deficiency 115200 Cardiomyopathy, dilated, 1A 115500Acatalasemia 115650 Cataract, anterior polar-1 115660 Cataract,cerulean, type 1 115665 Cataract, congenital, Volkmann type 116800Cataract, Marner type 116806 Colorectal cancer 116860 Cavernousangiomatous malformations 117700 [Hypoceruloplasminemia, hereditary]117700 Hemosiderosis, systemic, due to aceruloplasminemia 118210Charcot-Marie-Tooth neuropathy-2A 118425 Myotonia congenita, dominant,160800 118425 Myotonia congenita, recessive, 255700 118425 Myotonialevior, recessive 118485 Polycystic ovary syndrome withhyperandrogenemia 118504 Epilepsy, benign neonatal, type 1, 121200118504 Epilepsy, nocturnal frontal lobe, 600513 118511 Schizophrenia,neurophysiologic defect in 118800 Choreoathetosis, familial paroxysmal119300 van der Woude syndrome 120070 Alport syndrome, autosomalrecessive, 203780 120110 Metaphyseal chondrodysplasia, Schmid type120120 Epidermolysis bullosa dystrophica, dominant, 131750 120120Epidermolysis bullosa dystrophica, recessive, 226600 120120Epidermolysis bullosa, pretibial, 131850 120131 Alport syndrome,autosomal recessive, 203780 120131 Hematuria, familial benign 120140Osteoarthrosis, precocious 120140 SED congenita 120140 SMED Strudwicktype 120140 Stickler syndrome, type I 120140 Wagner syndrome, type II120140 Achondrogenesis-hypochondrogenesis, type II 120140 Kniestdysplasia 120150 Osteogenesis imperfecta, 4 clinical forms, 166200,166210, 259420, 166220 120150 Osteoporosis, idiopathic, 166710 120150Ehlers-Danlos syndrome, type VIIA1, 130060 120160 Osteogenesisimperfecta, 4 clinical forms, 166200, 166210, 259420, 166220 120160Osteoporosis, idiopathic, 166710 120160 Ehlers-Danlos syndrome, typeVIIA2, 130060 120160 Marfan syndrome, atypical 120180 Ehlers-Danlossyndrome, type III 120180 Ehlers-Danlos syndrome, type IV, 130050 120180Fibromuscular dysplasia of arteries, 135580 120180 Aneurysm, familial,100070 120190 Ehlers-Danlos syndrome, type I, 130000 120215Ehlers-Danlos syndrome, type I, 130000 120215 Ehlers-Danlos syndrome,type II, 130010 120220 Bethlem myopathy, 158810 120240 Bethlem myopathy,158810 120260 Epiphyseal dysplasia, multiple, type 2, 600204 120280Stickler syndrome, type III 120280 Marshall syndrome, 154780 120290OSMED syndrome, 215150 120290 Stickler syndrome, type II, 184840 120435Muir-Torre syndrome, 158320 120435 Colorectal cancer, hereditary,nonpolyposis, type 1 Ovarian cancer 120436 Muir-Torre family cancersyndrome, 158320 120436 Turcot syndrome with glioblastoma, 276300 120436Colorectal cancer, hereditary nonpolyposis, type 2 120550 C1qdeficiency, type A 120570 C1q deficiency, type B 120575 C1q deficiency,type C 120580 C1r/C1s is deficiency, combined 120620 SLE susceptibility120620 CR1 deficiency 120700 C3 deficiency 120810 C4 deficiency 120820C4 deficiency 120900 C5 deficiency 120920 Measles, susceptibility to120940 C9 deficiency 120950 C8 deficiency, type I 120960 C8 deficiency,type II 121014 Heterotaxia, visceroatrial, autosomal recessive 121050Contractural arachnodactyly, congenital 121360 Myeloid leukemia, acute,M4Eo subtype 121800 Corneal dystrophy, crystalline, Schnyder 122720Nicotine addiction, protection from 122720 Coumarin resistance, 122700123000 Craniometaphyseal dysplasia 123100 Craniosynostosis, type 1123101 Craniosynostosis, type 2 123270 [Creatine kinase, brain type,ectopic expression of] 123580 Cataract, congenital, autosomal dominant123620 Cataract, cerulean, type 2, 601547 123660 Cataract, Coppock-like123829 Melanoma 123940 White sponge nevus, 193900 124020 Mephenytoinpoor metabolizer 124030 Parkinsonism, susceptibility to 124030Debrisoquine sensitivity 124200 Darier disease (keratosis follicularis)125264 Leukemia, acute nonlymphocytic 125270 Porphyria, acute hepatic125270 Lead poisoning, susceptibility to 125370Dentatorubro-pallidoluysian atrophy 125490 Dentinogenesis imperfecta-1125660 Myopathy, desminopathic 125660 Cardiomyopathy 125852Insulin-dependent diabetes mellitus-2 126060 Anemia, megaloblastic, dueto DHFR deficiency 126337 Myxoid liposarcoma 126340 Xerodermapigmentosum, group D, 278730 126391 DNA ligase I deficiency 126451Schizophrenia, susceptibility to 126452 Autonomic nervous systemdysfunction 126452 [Novelty seeking personality] 126600 Drusen, radial,autosomal dominant 126650 Chloride diarrhea, congenital, Finnish type,214700 126650 Colon cancer 128100 Dystonia-1, torsion 129010 Neuropathy,congenital hypomyelinating, 1 129490 Ectodermal dysplasia-3, anhidrotic129900 EEC syndrome-1 130410 Glutaricaciduria, type IIB 130500Elliptocytosis-1 130650 Beckwith-Wiedemann syndrome 131100 Multipleendocrine neoplasia I 131100 Prolactinoma, hyperparathyroidism,carcinoid syndrome 131100 Carcinoid tumor of lung 131195 Hereditaryhemorrhagic telangiectasia-1, 187300 131210 Atherosclerosis,susceptibility to 131242 Shah-Waardenburg syndrome, 277580 131400Eosinophilia, familial 131440 Eosinophilic myeloproliferative disorder132700 Cylindromatosis 132810 Diphenylhydantoin toxicity 132810 Fetalhydantoin syndrome 133170 Erythremia 133171 [Erythrocytosis, familial],133100 133200 Erythrokeratodermia variabilis 133430 Breast cancer 133430Estrogen resistance 133450 Neuroepithelioma 133450 Ewing sarcoma 133510Trichothiodystrophy 133510 Xeroderma pigmentosum, group B 133550Dicarboxylicaminoaciduria, 222730 133700 Chondrosarcoma, 215300 133700Exostoses, multiple, type 1 133701 Exostoses, multiple, type 2 133780Vitreoretinopathy, exudative, familial 134370 Membroproliferativeglomerulonephritis 134370 Factor H deficiency 134370 Hemolytic-uremicsyndrome, 235400 134570 Factor XIIIA deficiency 134580 Factor XIIIBdeficiency 134637 Autoimmune lymphoproliferative syndrome 134790Hyperferritinemia-cataract syndrome, 600886 134820 Dysfibrinogenemia,alpha type, causing bleeding diathesis 134820 Dysfibrinogenemia, alphatype, causing recurrent thrombosis 134820 Amyloidosis, hereditary renal,105200 134830 Dysfibrinogenemia, beta type 134850 Dysfibrinogenemia,gamma type 134850 Hypofibrinogenemia, gamma type 134934 Thanatophoricdysplasia, types I and II, 187600 134934 Achondroplasia, 100800 134934Craniosynostosis, nonsyndromic 134934 Crouzon syndrome with acanthosisnigricans 134934 Hypochondroplasia, 146000 135300 Fibromatosis, gingival135600 Ehlers-Danlos syndrome, type X 135700 Fibrosis of extraocularmuscles, congenital, 1 135940 Ichthyosis vulgaris, 146700 136132[Fish-odor syndrome], 602079 136350 Pfeiffer syndrome, 101600 136435Ovarian dysgenesis, hypergonadotropic, with normal karyotype, 233300136530 Male infertility, familial 136836 Fucosyltransferase-6 deficiency137350 Amyloidosis, Finnish type, 105120 138030 [Hyperproglucagonemia]138033 Diabetes mellitus, type II 138040 Cortisol resistance 138079Hyperinsulinism, familial, 602485 138079 MODY, type 2, 125851 138130Hyperinsulinism-hyperammonemia syndrome 138140 Glucose transport defect,blood-brain barrier 138160 Diabetes mellitus, noninsulin-dependent138160 Fanconi-Bickel syndrome, 227810 138190 Diabetes mellitus,noninsulin-dependent 138250 P5CS deficiency 138300 Hemolytic anemia dueto glutathione reductase deficiency 138320 Hemolytic anemia due toglutathione peroxidase deficiency 138491 Startle disease, autosomalrecessive 138491 Startle disease/hyperekplexia, autosomal dominant,149400 138491 Hyperekplexia and spastic paraparesis 138570 Non-insulindependent diabetes mellitus, susceptibility to 138571 Glycogen synthase,liver, deficiency of, 240600 138700 [Apolipoprotein H deficiency] 138720Bernard-Soulier syndrome, type B 138971 Kostmann neutropenia, 202700138981 Pulmonary alveolar proteinosis, 265120 139130 Hypertension,essential, susceptibility to, 145500 139150 Basal cell carcinoma 139190Gigantism due to GHRF hypersecretion 139190 Isolated growth hormonedeficiency due to defect in GHRF 139191 Growth hormone deficientdwarfism 139250 Isolated growth hormone deficiency, Illig type withabsent GH and Kowarski type with bioinactive GH 139320 Pituitary ACTHsecreting adenoma 139320 Pseudohypoparathyroidism, type Ia, 103580139320 Somatotrophinoma 139320 McCune-Albright polyostotic fibrousdysplasia, 174800 139330 Night blindness, congenital stationary 139350Epidermolytic hyperkeratosis, 113800 139350 Keratoderma, palmoplantar,nonepidermolytic 139360 Pituitary ACTH-secreting adenoma 140100[Anhaptoglobinemia] 140100 [Hypohaptogloginemia] 141750Alpha-thalassemia/mental retardation syndrome, type 1 141800Methemoglobinemias, alpha- 141800 Thalassemias, alpha- 141800Erythremias, alpha- 141800 Heinz body anemias, alpha- 141850Thalassemia, alpha- 141850 Erythrocytosis 141850 Heinz body anemia141850 Hemoglobin H disease 141850 Hypochromic microcytic anemia 141900Methemoglobinemias, beta- 141900 Sickle cell anemia 141900 Thalassemias,beta- 141900 Erythremias, beta- 141900 HPFH, deletion type 141900 Heinzbody anemias, beta- 142000 Thalassemia due to Hb Lepore 142000Thalassemia, delta- 142200 HPFH, nondeletion type A 142250 HPFH,nondeletion type G 142270 Hereditary persistence of fetal hemoglobin142335 Hereditary persistence of fetal hemoglobin, heterocellular,Indian type 142470 [Hereditary persistence of fetal hemoglobin,heterocellular] 142640 Thrombophilia due to elevated HRG 142680 Periodicfever, familial 142857 Pemphigoid, susceptibility to 142858 Berylliumdisease, chronic, susceptibility to 142946 Holoprosencephaly-4 142959Hand-foot-uterus syndrome, 140000 142989 Synpolydactyly, type II, 186000143100 Huntington disease 143200 Wagner syndrome 143200 Erosivevitreoretinopathy 143890 Hypercholesterolemia, familial 144200Epidermolytic palmoplantar keratoderma 145001 Hyperparathyroidism-jawtumor syndrome 145260 Pseudohypoaldosteronism, type II 145410 Opitz Gsyndrome, type II 145505 Hypertension, essential 145981 Hypocalciurichypercalcemia, type II 146150 Hypomelanosis of Ito 146150 Hypomelanosisof Ito 146760 [IgG receptor I, phagocytic, familial deficiency of]146790 Lupus nephritis, susceptibility to 147050 Atopy 147141 Leukemia,acute lymphoblastic 147200 [Kappa light chain deficiency] 147280Hepatocellular carcinoma 147440 Growth retardation with deafness andmental retardation 147450 Amytrophic lateral sclerosis, due to SOD1deficiency, 105400 147545 Diabetes mellitus, noninsulin-dependent 147570Interferon, immune, deficiency 147660 Interferon, alpha, deficiency147670 Rabson-Mendenhall syndrome 147670 Diabetes mellitus,insulin-resistant, with acanthosis nigricans 147670 Leprechaunism 147730Interleukin-2 receptor, alpha chain, deficiency of 147781 Atopy,susceptibility to 147790 Leukemia, acute lymphocytic, with 4/11translocation 147791 Jacobsen syndrome 148040 Epidermolysis bullosasimplex, Koebner, Dowling-Meara, and Weber- Cockayne types, 131900,131760, 131800 148041 Pachyonychia congenita, Jadassohn-Lewandowskytype, 167200 148043 Meesmann corneal dystrophy, 122100 148065 Whitesponge nevus, 193900 148066 Epidermolysis bullosa simplex, Koebner,Dowling-Meara, and Weber- Cockayne types, 131900, 131760, 131800 148066Epidermolysis bullosa simplex, recessive, 601001 148067 Nonepidermolyticpalmoplantar keratoderma, 600962 148067 Pachyonychia congenita,Jadassohn-Lewandowsky type, 167200 148069 Pachyonychia congenita,Jackson-Lawler type, 167210 148070 Liver disease, susceptibility to,from hepatotoxins or viruses 148080 Epidermolytic hyperkeratosis, 113800148370 Keratolytic winter erythema 148500 Tylosis with esophageal cancer150000 Exertional myoglobinuria due to deficiency of LDH-A 150100Lactate dehydrogenase-B deficiency 150200 [Placental lactogendeficiency] 150210 Lactoferrin-deficient neutrophils, 245480 150230Langer-Giedion syndrome 150240 Cutis laxa, marfanoid neonatal type150250 Larsen syndrome, autosomal dominant 150270 Laryngeal adductorparalysis 150292 Epidermolysis bullosa, Herlitz junctional type, 226700150310 Epidermolysis bullosa, Herlitz junctional type, 226700 150310Epidermolysis bullosa, generalized atrophic benign, 226650 151385Leukemia, acute myeloid 151390 Leukemia, acute T-cell 151400Leukemia/lymphoma, B-cell, 1 151410 Leukemia, chronic myeloid 151440Leukemia, T-cell acute lymphoblastoid 151670 Hepatic lipase deficiency152200 Coronary artery disease, susceptibility to 152427 Long QTsyndrome-2 152445 Vohwinkel syndrome, 124500 152445 Erythrokeratoderma,progressive symmetric, 602036 152760 Hypogonadotropic hypogonadism dueto GNRH deficiency, 227200 152790 Precocious puberty, male, 176410152790 Leydig cell hypoplasia 153454 Ehlers-Danlos syndrome, type VI,225400 153455 Cutis laxa, recessive, type I, 219100 153700 Maculardystrophy, vitelliform type 153880 Macular dystrophy, dominant cystoid153900 Stargardt disease-2 154275 Malignant hyperthermia susceptibility2 154276 Malignant hyperthermia susceptibility 3 154400 Acrofacialdysostosis, Nager type 154500 Treacher Collins mandibulofacialdysostosis 154550 Carbohydrate-deficient glycoprotein syndrome, type Ib,602579 154705 Marfan syndrome, type II 155555 [Red hair/fair skin]155555 UV-induced skin damage, vulnerability to 155600 Malignantmelanoma, cutaneous 156225 Muscular dystrophy, congenitalmerosin-deficient 156232 Mesomelic dysplasia, Kantaputra type 156570Methylcobalamin deficiency, cbl G type 156600 Microcoria, congenital156845 Tietz syndrome, 103500 156845 Waardenburg syndrome, type IIA,193510 156845 Waardenburg syndrome/ocular albinism, digenic, 103470156850 Cataract, congenital, with microphthalmia 157147Abetalipoproteinemia, 200100 157170 Holoprosencephaly-2 157640 PEO withmitochondrial DNA deletions, type 1 157655 Lactic acidosis due to defectin iron-sulfur cluster of complex I 157900 Moebius syndrome 159000Muscular dystrophy, limb-girdle, type 1A 159001 Muscular dystrophy,limb-girdle, type 1B 159440 Charcot-Marie-Tooth neuropathy-1B, 118200159440 Dejerine-Sottas disease, myelin P-related, 145900 159440Hypomyelination, congenital 159555 Leukemia, myeloid/lymphoid ormixed-lineage 160777 Griscelli disease, 214450 160781 Cardiomyopathy,hypertrophic, mid-left ventricular chamber type 160900 Myotonicdystrophy 161015 Mitochondrial complex I deficiency, 252010 162100Neuralgic amyotrophy with predilection for brachial plexus 162200Neurofibromatosis, type 1 162200 Watson syndrome, 193520 162400Neuropathy, hereditary sensory and autonomic, type 1 163729Hypertension, pregnancy-induced 163890 Parkinson disease, type 1, 601508164009 Leukemia, acute promyelocytic, NUMA/RARA type 164040 Leukemia,acute promyelocytic, NPM/RARA type 164160 Obesity, severe, due to leptindeficiency 164200 Oculodentodigital dysplasia 164200 Syndactyly, typeIII, 186100 164500 Spinocerebellar ataxia-7 164731 Ovarian carcinoma,167000 164759 Ovarian carcinoma 164790 Colorectal cancer 164860 Renalcell carcinoma, papillary, familial and sporadic 164920 Piebaldism164920 Mast cell leukemia 164920 Mastocytosis with associatedhematologic disorder 164953 Liposarcoma 165240 Pallister-Hall syndrome,146510 165240 Postaxial polydactyly type A1, 174200 165240 Greigcephalopolysyndactyly syndrome, 175700 165320 Hepatocellular carcinoma165500 Optic atrophy 1 166600 Osteopetrosis, AD, type II 167000 Ovariancancer, serous 167250 Paget disease of bone 167409 Optic nerve colobomawith renal disease, 120330 167410 Rhabdomyosarcoma, alveolar, 268220167415 Hypothyroidism, congenital, due to thyroid dysgenesis orhypoplasia 168000 Paraganglioma, familial nonchromaffin, 1 168360Paraneoplastic sensory neuropathy 168450 Hypoparathyroidism, autosomaldominant 168450 Hypoparathyroidism, autosomal recessive 168461 Multiplemyeloma, 254250 168461 Parathyroid adenomatosis 1 168461 Centrocyticlymphoma 168468 Metaphyseal chondrodysplasia, Murk Jansen type, 156400168470 Humoral hypercalcemia of malignancy 168500 Parietal foramina169600 Hailey-Hailey disease 170261 Bare lymphocyte syndrome, type I,due to TAP2 deficiency 170500 Myotonia congenita, atypicalacetazolamide-responsive 170500 Paramyotonia congenita, 168300 170500Hyperkalemic periodic paralysis 170650 Periodontitis, juvenile 170995Zellweger syndrome-2 171050 Colchicine resistance 171060 Cholestasis,progressive familial intrahepatic, type III, 602347 171190 Hypertension,essential, 145500 171650 Lysosomal acid phosphatase deficiency 171760Hypophosphatasia, adult, 146300 171760 Hypophosphatasia, infantile,241500 171860 Hemolytic anemia due to phosphofructokinase deficiency172400 Hemolytic anemia due to glucosephosphate isomerase deficiency172400 Hydrops fetalis, one form 172411 Colorectal cancer, resistance to172430 Enolase deficiency 172471 Glycogenosis, hepatic, autosomal 172490Phosphorylase kinase deficiency of liver and muscle, 261750 173350Plasminogen Tochigi disease 173350 Plasminogen deficiency, types I andII 173350 Thrombophilia, dysplasminogenemic 173360 Thrombophilia due toexcessive plasminogen activator inhibitor 173360 Hemorrhagic diathesisdue to PAI1 deficiency 173370 Plasminogen activator deficiency 173470Glanzmann thrombasthenia, type B 173610 Platelet alpha/delta storagepool deficiency 173850 Polio, susceptibility to 173870 Xerodermapigmentosum 173870 Fanconi anemia 173910 Polycystic kidney disease,adult, type II 174000 Medullary cystic kidney disease, AD 174810Osteolysis, familial expansile 174900 Polyposis, juvenile intestinal175100 Turcot syndrome, 276300 175100 Adenomatous polyposis coli 175100Adenomatous polyposis coli, attenuated 175100 Colorectal cancer 175100Desmoid disease, hereditary, 135290 175100 Gardner syndrome 176000Porphyria, acute intermittent 176100 Porphyria cutanea tarda 176100Porphyria, hepatoerythropoietic 176260 Episodic ataxia/myokymiasyndrome, 160120 176261 Jervell and Lange-Nielsen syndrome, 220400176270 Prader-Willi syndrome 176300 [Dystransthyretinemichyperthyroxinemia] 176300 Carpal tunnel syndrome, familial 176300Amyloid neuropathy, familial, several allelic types 176300 Amyloidosis,senile systemic 176450 Sacral agenesis-1 176730 Diabetes mellitus, rareform 176730 Hyperproinsulinemia, familial 176730 MODY, one form 176801Metachromatic leukodystrophy due to deficiency of SAP-1 176801 Gaucherdisease, variant form 176830 Obesity, adrenal insufficiency, and redhair 176830 ACTH deficiency 176860 Purpura fulminans, neonatal 176860Thrombophilia due to protein C deficiency 176880 Protein S deficiency176930 Dysprothrombinemia 176930 Hypoprothrombinemia 176943 Apertsyndrome, 101200 176943 Pfeiffer syndrome, 101600 176943 Beare-Stevensoncutis gyrata syndrome, 123790 176943 Crouzon craniofacial dysostosis,123500 176943 Jackson-Weiss syndrome, 123150 176947 Selective T-celldefect 176960 Pituitary tumor, invasive 177070 Spherocytosis,hereditary, Japanese type 177070 Hermansky-Pudlak syndrome, 203300177400 Apnea, postanesthetic 177900 Psoriasis susceptibility-1 178300Ptosis, hereditary congenital, 1 178600 Pulmonary hypertension, familialprimary 178640 Pulmonary alveolar proteinosis, congenital, 265120 179095Male infertility 179450 Ragweed sensitivity 179605 Retinitis pigmentosa,digenic 179605 Retinitis pigmentosa-7, peripherin-related 179605Retinitis punctata albescens 179605 Butterfly dystrophy, retinal 179605Macular dystrophy 179615 Reticulosis, familial histiocytic, 267700179615 Severe combined immunodeficiency, B cell-negative, 601457 179616Severe combined immunodeficiency, B cell-negative, 601457 179755 Renalcell carcinoma, papillary, 1 179820 [Hyperproreninemia] 180020 Retinalcone dystrophy-1 180069 Retinal dystrophy, autosomal recessive,childhood-onset 180069 Retinitis pigmentosa-20 180069 Leber congenitalamaurosis-2, 204100 180071 Retinitis pigmentosa, autosomal recessive180072 Night blindness, congenital stationary, type 3, 163500 180072Retinitis pigmentosa, autosomal recessive 180100 Retinitis pigmentosa-1180104 Retinitis pigmentosa-9 180105 Retinitis pigmentosa-10 180200Osteosarcoma, 259500 180200 Pinealoma with bilateral retinoblastoma180200 Retinoblastoma 180200 Bladder cancer, 109800 180240 Leukemia,acute promyelocytic 180250 Retinol binding protein, deficiency of 180297Anemia, hemolytic, Rh-null, suppressor type, 268150 180380 Nightblindness, congenital stationery, rhodopsin-related 180380 Retinitispigmentosa, autosomal recessive 180380 Retinitis pigmentosa-4, autosomaldominant 180381 Oguchi disease-2, 258100 180385 Leukemia, acute T-cell180721 Retinitis pigmentosa, digenic 180840 Susceptibility to IDDM180860 Russell-Silver syndrome 180901 Malignant hyperthermiasusceptibility 1, 145600 180901 Central core disease, 117000 181030Salivary gland pleomorphic adenoma 181031 Oguchi disease-1, 258100181405 Scapuloperoneal spinal muscular atrophy, New England type 181430Scapuloperoneal syndrome, myopathic type 181460 Schistosoma mansoni,susceptibility/resistance to 181510 Schizophrenia 181600 Sclerotylosis182138 Anxiety-related personality traits 182279 Prader-Willi syndrome182280 Small-cell cancer of lung 182380 Glucose/galactose malabsorption182381 Renal glucosuria, 253100 182452 Lung cancer, small cell 182500Cataract, congenital 182600 Spastic paraplegia-3A 182601 Spasticparaplegia-4 182860 Pyropoikilocytosis 182860 Spherocytosis, recessive182860 Elliptocytosis-2 182870 Spherocytosis-1 182870 Elliptocytosis-3182870 Anemia, neonatal hemolytic, fatal and near-fatal 182900Spherocytosis-2 183600 Split hand/foot malformation, type 1 185000Stomatocytosis I 185430 Atherosclerosis, susceptibility to 185470Myopathy due to succinate dehydrogenase deficiency 185800 Symphalangism,proximal 186580 Arthrocutaneouveal granulomatosis 186740Immunodeficiency due to defect in CD3-gamma 186770 Leukemia, T-cellacute lymphocytic 186780 CD3, zeta chain, deficiency 186830Immunodeficiency, T-cell receptor/CD3 complex 186860 Leukemia/lymphoma,T-cell 186880 Leukemia/lymphoma, T-cell 186921 Leukemia, T-cell acutelymphoblastic 187040 Leukemia-1, T-cell acute lymphoblastic 1876806-mercaptopurine sensitivity 188025 Thrombocytopenia, Paris-Trousseautype 188070 Bleeding disorder due to defective thromboxane A2 receptor188450 Goiter, adolescent multinodular 188450 Goiter, nonendemic, simple188450 Hypothyroidism, hereditary congenital 188540 Hypothyroidism,nongoitrous 188826 Sorsby fundus dystrophy, 136900 189800Preeclampsia/eclampsia 189980 Leukemia, chronic myeloid 190000Atransferrinemia 190020 Bladder cancer, 109800 190040 Meningioma,SIS-related 190040 Dermatofibrosarcoma protuberans 190040 Giant-cellfibroblastoma 190100 Geniospasm 190160 Thyroid hormone resistance,274300, 188570 190182 Colon cancer 190182 Colorectal cancer, familialnonpolyposis, type 6 190195 Ichthyosiform erythroderma, congenital,242100 190195 Ichthyosis, lamellar, autosomal recessive, 242300 190198Leukemia, T-cell acute lymphoblastic 190450 Hemolytic anemia due totriosephosphate isomerase deficiency 190605 Triphalangealthumb-polysyndactyly syndrome 190685 Down syndrome 190900Colorblindness, tritan 191010 Cardiomyopathy, familial hypertrophic, 3,115196 191030 Nemaline myopathy-1, 161800 191044 Cardiomyopathy,familial hypertrophic 191045 Cardiomyopathy, familial hypertrophic, 2,115195 191092 Tuberous sclerosis-2 191100 Tuberous sclerosis-1 191170Colorectal cancer, 114500 191170 Li-Fraumeni syndrome 191181 Cervicalcarcinoma 191290 Segawa syndrome, recessive 191315 Insensitivity topain, congenital, with anhidrosis, 256800 191540 [Urate oxidasedeficiency] 192090 Ovarian carcinoma 192090 Breast cancer, lobular192090 Endometrial carcinoma 192090 Gastric cancer, familial, 137215192340 Diabetes insipidus, neurohypophyseal, 125700 192500 Jervell andLange-Nielsen syndrome, 220400 192500 Long QT syndrome-1 192974 Neonatalalloimmune thrombocytopenia 192974 Glycoprotein Ia deficiency 193100Hypophosphatemic rickets, autosomal dominant 193235 Vitreoretinopathy,neovascular inflammatory 193300 Renal cell carcinoma 193300 vonHippel-Lindau syndrome 193400 von Willebrand disease 193500Rhabdomyosarcoma, alveolar, 268220 193500 Waardenburg syndrome, type I193500 Waardenburg syndrome, type III, 148820 193500Craniofacial-deafness-hand syndrome, 122880 194070 Wilms tumor, type 1194070 Denys-Drash syndrome 194070 Frasier syndrome, 136680 194071 Wilmstumor, type 2 194071 Adrenocortical carcinoma, hereditary, 202300 194190Wolf-Hirschhorn syndrome 200150 Choreoacanthocytosis 200990 Acrocallosalsyndrome 201450 Acyl-CoA dehydrogenase, medium chain, deficiency of201460 Acyl-CoA dehydrogenase, long chain, deficiency of 201470 Acyl-CoAdehydrogenase, short-chain, deficiency of 201910 Adrenal hyperplasia,congenital, due to 21-hydroxylase deficiency 202110 Adrenal hyperplasia,congenital, due to 17-alpha-hydroxylase deficiency 203100 Waardenburgsyndrome/ocular albinism, digenic, 103470 203100 Albinism,oculocutaneous, type IA 203200 Albinism, ocular, autosomal recessive203200 Albinism, oculocutaneous, type II 203300 Hermansky-Pudlaksyndrome 203310 Ocular albinism, autosomal recessive 203500 Alkaptonuria203740 Alpha-ketoglutarate dehydrogenase deficiency 2037503-ketothiolase deficiency 203800 Alstrom syndrome 204500Ceroid-lipofuscinosis, neuronal 2, classic late infantile 205100Amyotrophic lateral sclerosis, juvenile 207750 Hyperlipoproteinemia,type Ib 207800 Argininemia 208100 Arthrogryposis multiplex congenita,neurogenic 208250 Jacobs syndrome 208400 Aspartylglucosaminuria 209901Bardet-Biedl syndrome 1 211420 Breast cancer, ductal 212138Carnitine-acylcarnitine translocase deficiency 214300 Klippel-Feilsyndrome 214400 Charcot-Marie-Tooth neuropathy-4A 214500 Chediak-Higashisyndrome 215700 Citrullinemia 216550 Cohen syndrome 216900 Achromatopsia216950 C1r/C1s deficiency, combined 217000 C2 deficiency 217050 C6deficiency 217050 Combined C6/C7 deficiency 217070 C7 deficiency 217800Macular corneal dystrophy 218000 Andermann syndrome 218030 Apparentmineralocorticoid excess, hypertension due to 219800 Cystinosis,nephropathic 221770 Polycystic lipomembranous osteodysplasia withsclerosing leukencephalopathy 221820 Gliosis, familial progressivesubcortical 222100 Diabetes mellitus, insulin-dependent-1 222600Atelosteogenesis II, 256050 222600 Achondrogenesis Ib, 600972 222600Diastrophic dysplasia 222700 Lysinuric protein intolerance 222800Hemolytic anemia due to bisphosphoglycerate mutase deficiency 222900Sucrose intolerance 223000 Lactase deficiency, adult, 223100 223000Lactase deficiency, congenital 223360 Dopamine-beta-hydroxylasedeficiency 223900 Dysautonomia, familial 224100 Congenitaldyserythropoietic anemia II 224120 Dyserythropoietic anemia, contenital,type I 225500 Ellis-van Creveld syndrome 227220 [Eye color, brown]227500 Factor VII deficiency 227600 Factor X deficiency 227646 Fanconianemia, type D 227650 Fanconi anemia, type A 228960 [Kininogendeficiency] 229300 Friedreich ataxia 229300 Friedreich ataxia withretained reflexes 229600 Fructose intolerance 229700Fructose-bisphosphatase deficiency 229800 [Fructosuria] 230000Fucosidosis 230200 Galactokinase deficiency with cataracts 230350Galactose epimerase deficiency 230400 Galactosemia 230450 Hemolyticanemia due to gamma-glutamylcysteine synthetase deficiency 230800Gaucher disease 230800 Gaucher disease with cardiovascular calcification231550 Achalasia-addisonianism-alacrimia syndrome 231670Glutaricaciduria, type I 231680 Glutaricaciduria, type IIA 231950Glutathioninuria 232000 Propionicacidemia, type I or pccA type 232050Propionicacidemia, type II or pccB type 232300 Glycogen storage diseaseII 232400 Glycogen storage disease IIIa 232400 Glycogen storage diseaseIIIb 232500 Glycogen storage disease IV 232600 McArdle disease 232700Glycogen storage disease VI 232800 Glycogen storage disease VII 233100[Renal glucosuria] 233700 Chronic granulomatous disease due todeficiency of NCF-1 233710 Chronic granulomatous disease due todeficiency of NCF-2 234000 Factor XII deficiency 234200Neurodegeneration with brain iron accumulation 235200 Hemochromatosis235800 [Histidinemia] 236100 Holoprosencephaly-1 236200 Homocystinuria,B6-responsive and nonresponsive types 236730 Urofacial syndrome 237300Carbamoylphosphate synthetase I deficiency 238300 Hyperglycinemia,nonketotic, type I 238310 Hyperglycinemia, nonketotic, type II 238600Chylomicronemia syndrome, familial 238600 Combined hyperlipemia,familial 238600 Hyperlipoproteinemia I 238600 Lipoprotein lipasedeficiency 238970 HHH syndrome 239100 Van Buchem disease 239500Hyperprolinemia, type I 240300 Autoimmune polyglandular disease, type I240400 Scurvy 243500 Isovalericacidemia 245000 Papillon-Lefevre syndrome245050 Ketoacidosis due to SCOT deficiency 245200 Krabbe disease 245349Lacticacidemia due to PDX1 deficiency 245900 Norum disease 245900Fish-eye disease 246450 HMG-CoA lyase deficiency 246530 Leukotriene C4synthase deficiency 246600 Pancreatic lipase deficiency 246900 Lipoamidedehydrogenase deficiency 247200 Miller-Dieker lissencephaly syndrome247640 Leukemia, acute lymphoblastic 248510 Mannosidosis, beta- 248600Maple syrup urine disease, type Ia 248610 Maple syrup urine disease,type II 248611 Maple syrup urine disease, type Ib 249000 Meckel syndrome249270 Thiamine-responsive megaloblastic anemia 250100 Metachromaticleukodystrophy 250250 Cartilage-hair hypoplasia 250790 Methemoglobinemiadue to cytochrome b5 deficiency 250800 Methemoglobinemia, type I 250800Methemoglobinemia, type II 251000 Methylmalonicaciduria, mutasedeficiency type 251600 Microphthalmia, autosomal recessive 252500Mucolipidosis II 252500 Mucolipidosis III 252800 MucopolysaccharidosisIh 252800 Mucopolysaccharidosis Ih/s 252800 Mucopolysaccharidosis Is252900 Sanfilippo syndrome, type A 252940 Sanfilippo syndrome, type D253000 Mucopolysaccharidosis IVA 253200 Maroteaux-Lamy syndrome, severalforms 253250 Mulibrey nanism 253270 Multiple carboxylase deficiency,biotin-responsive 253601 Miyoshi myopathy, 254130 253601 Musculardystrophy, limb-girdle, type 2B 253800 Walker-Warburg syndrome, 236670253800 Fukuyama type congenital muscular dystrophy 254210 Myastheniagravis, familial infantile 254770 Epilepsy, juvenile myoclonic 254780Myoclonus epilepsy, Lafora type 255800 Schwartz-Jampel syndrome 256030Nemaline myopathy-2 256100 Nephronophthisis, juvenile 256540Galactosialidosis 256550 Sialidosis, type I 256550 Sialidosis, type II256700 Neuroblastoma 256731 Ceroid-lipofuscinosis, neuronal-5, variantlate infantile 256850 Giant axonal neuropathy-1 257200 Niemann-Pickdisease, type A 257200 Niemann-Pick disease, type B 257220 Niemann-Pickdisease, type C 257220 Niemann-Pick disease, type D, 257250 2585013-methylglutaconicaciduria, type III 258870 Gyrate atrophy of choroidand retina with ornithinemia, B6 responsive or unresponsive 259700Osteopetrosis, recessive 259730 Renal tubular acidosis-osteopetrosissyndrome 259770 Osteoporosis-pseudoglioma syndrome 259900 Hyperoxaluria,primary, type 1 261510 Pseudo-Zellweger syndrome 261515 Peroxisomalbifunctional enzyme deficiency 261600 Phenylketonuria 261600[Hyperphenylalaninemia, mild] 261640 Phenylketonuria due to PTSdeficiency 261670 Myopathy due to phosphoglycerate mutase deficiency262000 Bjornstad syndrome 263200 Polycystic kidney disease, autosomalrecessive 263700 Porphyria, congenital erythropoietic 264300Pseudohermaphroditism, male, with gynecomastia 264470Adrenoleukodystrophy, pseudoneonatal 264700 Pseudo-vitamin D dependencyrickets 1 266100 Pyridoxine dependency with seizures 266150 Pyruvatecarboxylase deficiency 266200 Anemia, hemolytic, due to PK deficiency266300 [Hair color, red] 266600 Inflammatory bowel disease-1 267750Knobloch syndrome 268900 [Sarcosinemia] 270100 Situs inversus viscerum270800 Spastic paraplegia-5A 271245 Spinocerebellar ataxia-8, infantile,with sensory neuropathy 271900 Canavan disease 272750GM2-gangliosidosis, AB variant 272800 Tay-Sachs disease 272800 [Hex Apseudodeficiency] 272800 GM2-gangliosidosis, juvenile, adult 273300 Malegerm cell tumor 273800 Thrombocytopenia, neonatal alloimmune 273800Glanzmann thrombasthenia, type A 274180 Thromboxane synthase deficiency274270 Thymine-uraciluria 274270 Fluorouracil toxicity, sensitivity to274600 Pendred syndrome 274600 Deafness, autosomal recessive 4 275350Transcobalamin II deficiency 276000 Pancreatitis, hereditary, 167800276000 Trypsinogen deficiency 276600 Tyrosinemia, type II 276700Tyrosinemia, type I 276900 Usher syndrome, type 1A 276901 Ushersyndrome, type 2 276902 Usher syndrome, type 3 276903 Usher syndrome,type 1B 276903 Deafness, autosomal dominant 11, neurosensory, 601317276903 Deafness, autosomal recessive 2, neurosensory, 600060 276904Usher syndrome, type 1C 277700 Werner syndrome 277730 Wernicke-Korsakoffsyndrome, susceptibility to 278000 Wolman disease 278000 Cholesterylester storage disease 278250 Wrinkly skin syndrome 278300 Xanthinuria,type I 278700 Xeroderma pigmentosum, group A 278760 Xerodermapigmentosum, group F 300008 Nephrolithiasis, type I, 310468 300008Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis300008 Dent disease, 300009 300008 Hypophosphatemia, type III 300011Menkes disease, 309400 300011 Occipital horn syndrome, 304150 300011Cutis laxa, neonatal 300031 Mental retardation, X-linked, FRAXF type300032 Alpha-thalassemia/mental retardation syndrome, type 2, 301040300032 Juberg-Marsidi syndrome, 309590 300037 Simpson dysmorphiasyndrome, 312870 300039 Deafness, X-linked 3, conductive, with stapesfixation, 304400 300044 Wernicke-Korsakoff syndrome, susceptibility to300046 Mental retardation, X-linked 23, nonspecific 300047 Mentalretardation, X-linked 20 300048 Intestinal pseudoobstruction, neuronal,X-linked 300049 Nodular heterotopia, bilateral periventricular 300049BPNH/MR syndrome 300055 Mental retardation with psychosis, pyramidalsigns, and macroorchidism 300062 Mental retardation, X-linked 14 300071Night blindness, congenital stationary, type 2 300076 Woodneuroimmunologic syndrome 300077 Mental retardation, X-linked 29 300088Epilepsy, female restricted, with mental retardation 300100Adrenoleukodystrophy 300100 Adrenomyeloneuropathy 300104 Mentalretardation, X-linked nonspecific, 309541 300110 Night blindness,congenital stationary, X-linked incomplete, 300071 300123 Mentalretardation with isolated growth hormone deficiency 300126 Dyskeratosiscongenita-1, 305000 300136 Diabetes mellitus, insulin-dependent,X-linked, susceptibility to 300300 XLA and isolated growth hormonedeficiency, 307200 300300 Agammaglobulinemia, type 1, X-linked 300600Ocular albinism, Forsius-Eriksson type 301000 Thrombocytopenia,X-linked, 313900 301000 Wiskott-Aldrich syndrome 301200 Amelogenesisimperfecta 301201 Amelogenesis imperfecta-3, hypoplastic type 301300Anemia, sideroblastic/hypochromic 301310 Anemia, sideroblastic, withspinocerebellar ataxia 301500 Fabry disease 301590 Anophthalmos-1 301830Arthrogryposis, X-linked (spinal muscular atrophy, infantile, X-linked)301835 Arts syndrome 301845 Bazex syndrome 301900Borjeson-Forssman-Lehmann syndrome 302060 Noncompaction of leftventricular myocardium, isolated 302060 Barth syndrome 302060Cardiomyopathy, X-linked dilated, 300069 302060 Endocardialfibroelastosis-2 302350 Nance-Horan syndrome 302960 Chondrodysplasiapunctata, X-linked dominant 303400 Cleft palate, X-linked 303630 Alportsyndrome, 301050 303630 Leiomyomatosis-nephropathy syndrome, 308940303631 Leiomyomatosis, diffuse, with Alport syndrome 303700Colorblindness, blue monochromatic 303800 Colorblindness, deutan 303900Colorblindness, protan 304020 Cone dystrophy, progressive X-linked, 1304040 Charcot-Marie-Tooth neuropathy, X-linked-1, dominant, 302800304340 Mental retardation, X-linked, syndromic-5, with Dandy-Walkermalformation, basal ganglia disease, and seizures 304500 Deafness,X-linked 2, perceptive congenital 304700 Mohr-Tranebjaerg syndrome304700 Deafness, X-linked 1, progressive 304700 Jensen syndrome, 311150304800 Diabetes insipidus, nephrogenic 305100 Anhidrotic ectodermaldysplasia 305400 Aarskog-Scott syndrome 305450 FG syndrome 305900 Favism305900 G6PD deficiency 305900 Hemolytic anemia due to G6PD deficiency306700 Hemophilia A 306900 Hemophilia B 306995 [Homosexuality, male]307150 Hypertrichosis, congenital generalized 307700 Hypoparathyroidism,X-linked 308000 HPRT-related gout 308000 Lesch-Nyhan syndrome 308230Immunodeficiency, X-linked, with hyper-IgM 308240 Lymphoproliferativesyndrome, X-linked 308300 Incontinentia pigmenti, sporadic type 308310Incontinentia pigmenti, familial 308380 Severe combinedimmunodeficiency, X-linked, 300400 308380 Combined immunodeficiency,X-linked, moderate, 312863 308840 Spastic paraplegia, 312900 308840Hydrocephalus due to aqueductal stenosis, 307000 308840 MASA syndrome,303350 309000 Lowe syndrome 309200 Manic-depressive illness, X-linked309300 Megalocornea, X-linked 309470 Mental retardation, X-linked,syndromic-3, with spastic diplegia 309500 Renpenning syndrome-1 309545Mental retardation, X-linked nonspecific, with aphasia 309548 Mentalretardation, X-linked, FRAXE type 309555 Gustavson syndrome 309605Mental retardation, X-linked, syndromic-4, with congenital contracturesand low fingertip arches 309610 Mental retardation, X-linked,syndromic-2, with dysmorphism and cerebral atrophy 309620 Mentalretardation-skeletal dysplasia 309850 Brunner syndrome 309900Mucopolysaccharidosis II 310300 Emery-Dreifuss muscular dystrophy 310400Myotubular myopathy, X-linked 310460 Myopia-1 310460 Bornholm eyedisease 310490 Cowchock syndrome 310500 Night blindness, congenitalstationary, type 1 311050 Optic atrophy, X-linked 311200Oral-facial-digital syndrome 1 311300 Otopalatodigital syndrome, type I311510 Waisman parkinsonism-mental retardation syndrome 311800Myoglobinuria/hemolysis due to PGK deficiency 311800 Hemolytic anemiadue to PGK deficiency 311850 Phosphoribosyl pyrophosphatesynthetase-related gout 311870 Muscle glycogenosis 312000Panhypopituitarism, X-linked 312040 N syndrome, 310465 312060 Properdindeficiency, X-linked 312080 Pelizaeus-Merzbacher disease 312080 Spasticparaplegia-2, 312920 312600 Retinitis pigmentosa-2 312760 Turnersyndrome 313350 Split hand/foot malformation, type 2 313850Thoracoabdominal syndrome 314200 [Euthyroidal hyper- andhypothyroxinemia] 314250 Dystonia-3, torsion, with parkinsonism,Filipino type 314300 Goeminne TKCR syndrome 314400 Cardiac valvulardysplasia-1 314580 Wieacker-Wolff syndrome 600020 Prostate cancer,176807 600035 Schizencephaly 600040 Colorectal cancer 600044Thrombocythemia, essential, 187950 600045 Xeroderma pigmentosum, groupE, subtype 2 600048 Breast cancer-3 600059 Retinitis pigmentosa-13600065 Leukocyte adhesion deficiency, 116920 600079 Colon cancer 600095Split hand/foot malformation, type 3 600101 Deafness, autosomal dominant2 600105 Retinitis pigmentosa-12, autosomal recessive 600119 Musculardystrophy, Duchenne-like, type 2 600119 Adhalinopathy, primary 600138Retinitis pigmentosa-11 600140 Rubenstein-Taybi syndrome, 180849 600143Epilepsy, progressive, with mental retardation 600151 Bardet-Biedlsyndrome 3 600160 Melanoma, 155601 600163 Long QT syndrome-3 600173SCID, autosomal recessive, T-negative/B-positive type 600175 Spinalmuscular atrophy, congenital nonprogressive, of lower limbs 600179 Lebercongenital amaurosis, type I, 204000 600184 Carnitine acetyltransferasedeficiency 600185 Pancreatic cancer 600185 Breast cancer 2, early onset600194 Ichthyosis bullosa of Siemens, 146800 600202 Dyslexia, specific,2 600211 Cleidocranial dysplasia, 119600 600221 Venous malformations,multiple cutaneous and mucosal, 600195 600223 Spinocerebellar ataxia-4600225 Phenylketonuria, atypical, due to GCH1 deficiency, 233910 600225Dystonia, DOPA-responsive, 128230 600228 Pseudohypoaldosteronism, typeI, 264350 600231 Palmoplantar keratoderma, Bothnia type 600234 HMG-CoAsynthease-2 deficiency 600243 Temperature-sensitive apoptosis 600258Colorectal cancer, hereditary nonpolyposis, type 3 600259 Turcotsyndrome with glioblastoma, 276300 600259 Colorectal cancer, hereditarynonpolyposis, type 4 600261 Ehlers-Danlos-like syndrome 600266Resistance/susceptibility to TB, etc. 600273 Polycystic kidney disease,infantile severe, with tuberous sclerosis 600276 Cerebral arteriopathywith subcortical infarcts and leukoencephalopathy, 125310 600281Non-insulin-dependent diabetes mellitus, 125853 600281 MODY, type 1,125850 600309 Atrioventricular canal defect-1 600310Pseudoachondroplasia, 177170 600310 Epiphyseal dysplasia, multiple 1,132400 600319 Diabetes mellitus, insulin-dependent, 4 600320Insulin-dependent diabetes mellitus-5 600321 Diabetes mellitus,insulin-dependent, 7 600332 Rippling muscle disease-1 600354 Spinalmuscular atrophy-1, 253300 600354 Spinal muscular atrophy-2, 253550600354 Spinal muscular atrophy-3, 253400 600364 Cone dystrophy-3, 602093600374 Bardet-Biedl syndrome 4 600414 Adrenoleukodystrophy, neonatal,202370 600415 Ataxia with isolated vitamin E deficiency, 277460 600429[Ii blood group, 110800] 600509 Persistent hyperinsulinemic hypoglycemiaof infancy, 256450 600510 Pigment dispersion syndrome 600511Schizophrenia-3 600512 Epilepsy, partial 600525 Trichodontoosseoussyndrome, 190320 600528 CPT deficiency, hepatic, type I, 255120 600536Myopathy, congenital 600542 Chondrosarcoma, extraskeletal myxoid 600584Atrial septal defect with atrioventricular conduction defects, 108900600593 Craniosynostosis, Adelaide type 600617 Lipoid adrenalhyperplasia, 201710 600618 Leukemia, acute lymphoblastic 600623 Prostatecancer, 176807 600624 Cone-rod retinal dystrophy-1 600631 Enuresis,nocturnal, 1 600650 Myopathy due to CPT II deficiency, 255110 600650 CPTdeficiency, hepatic, type II, 600649 600698 Salivary adenoma 600698Uterine leiomyoma 600698 Lipoma 600698 Lipomatosis, mutiple, 151900600700 Lipoma 600701 Lipoma 600722 Ceroid lipofuscinosis, neuronal,variant juvenile type, with granular osmiophilic deposits 600722 Ceroidlipofuscinosis, neuronal-1, infantile, 256730 600725Holoprosencephaly-3, 142945 600759 Alzheimer disease-4 600760Pseudohypoaldosteronism, type I, 264350 600760 Liddle syndrome, 177200600761 Pseudohypoaldosteronism, type I, 264350 600761 Liddle syndrome,177200 600795 Dementia, familial, nonspecific 600807 Bronchial asthma600808 Enuresis, nocturnal, 2 600811 Xeroderma pigmentosum, group E,DDB-negative subtype, 278740 600837 Hirschsprung disease, 142623 600839Bartter syndrome, 241200 600850 Schizophrenia disorder-4 600852Retinitis pigmentosa-17 600856 Beckwith-Wiedemann syndrome, 130650600881 Cataract, congenital, zonular, with sutural opacities 600882Charcot-Marie-Tooth neuropathy-2B 600883 Diabetes mellitus,insulin-dependent, 8 600887 Endometrial carcinoma 600897 Cataract,zonular pulverulent-1, 116200 600900 Muscular dystrophy, limb-girdle,type 2E 600918 Cystinuria, type III 600923 Porphyria variegata, 176200600937 Persistent hyperinsulinemic hypoglycemia of infancy, 256450600946 Short stature, autosomal dominant, with normal serum growthhormone binding protein 600946 Short stature, idiopathic 600946 Larondwarfism, 262500 600956 Persistent Mullerian duct syndrome, type II,261550 600957 Persistent Mullerian duct syndrome, type I, 261550 600958Cardiomyopathy, familial hypertrophic, 4, 115197 600965 Deafness,autosomal dominant 6 600968 Gitelman syndrome, 263800 600971 Deafness,autosomal recessive 6 600974 Deafness, autosomal recessive 7 600975Glaucoma 3, primary infantile, B 600977 Cone dystrophy, progressive600983 Pseudohypoaldosteronism type I, autosomal dominant, 177735 600993Pancreatic cancer 600995 Nephrotic syndrome, idiopathic,steroid-resistant 600996 Arrhythmogenic right ventricular dysplasia-2600998 Bleeding diathesis due to GNAQ deficiency 601002 5-oxoprolinuria,266130 601002 Hemolytic anemia due to glutathione synthetase deficiency,231900 601011 Spinocerebellar ataxia-6, 183086 601011 Cerebellar ataxia,pure 601011 Episodic ataxia, type 2, 108500 601011 Hemiplegic migraine,familial, 141500 601071 Deafness, autosomal recessive 9 601072 Deafness,autosomal recessive 8 601090 Iridogoniodysgenesis, 601631 601105Pycnodysostosis, 265800 601107 Dubin-Johnson syndrome, 237500 601130Tolbutamide poor metabolizer 601145 Epilepsy, progressive myoclonic 1,254800 601146 Brachydactyly, type C, 113100 601146 Acromesomelicdysplasia, Hunter-Thompson type, 201250 601146 Chondrodysplasia, Grebetype, 200700 601154 Cardiomyopathy, dilated, 1E 601199 Neonatalhyperparathyroidism, 239200 601199 Hypocalcemia, autosomal dominant,601198 601199 Hypocalciuric hypercalcemia, type I, 145980 601202Cataract, anterior polar-2 601208 Insulin-dependent diabetes mellitus-11601226 Progressive external ophthalmoplegia, type 2 601238 Cerebellarataxia, Cayman type 601267 HIV infection, susceptibility/resistence to601277 Ichthyosis, lamellar, type 2 601284 Hereditary hemorrhagictelangiectasia-2, 600376 601313 Polycystic kidney disease, adult type I,173900 601316 Deafness, autosomal dominant 10 601318 Diabetes mellitus,insulin-dependent, 13 601362 DiGeorge syndrome/velocardiofacial syndromecomplex-2 601363 Wilms tumor, type 4 601373 HIV infection,susceptibility/resistance to 601382 Charcot-Marie-Tooth neuropathy-4B601385 Prostate cancer 601387 Breast cancer 601399 Platelet disorder,familial, with associated myeloid malignancy 601402 Leukemia, myeloid,acute 601406 B-cell non-Hodgkin lymphoma, high-grade 601410 Diabetesmellitus, transient neonatal 601411 Muscular dystrophy, limb-girdle,type 2F, 601287 601412 Deafness, autosomal dominant 7 601414 Retinitispigmentosa-18 601458 Inflammatory bowel disease-2 601471 Moebiussyndrome-2 601493 Cardiomyopathy, dilated 1C 601494 Cardiomyopathy,familial, dilated-2 601498 Peroxisomal biogenesis disorder,complementation group 4 601518 Prostate cancer, hereditary, 1, 176807601545 Lissencephaly-1 601556 Spinocerebellar ataxia-1, 164400 601567Combined factor V and VIII deficiency, 227300 601596 Charcot-Marie-Toothneuropathy, demyelinating 601604 Mycobacterial and salmonellainfections, susceptibility to 601606 Trichoepithelioma, multiplefamilial 601620 Holt-Oram syndrome, 142900 601621 Ulnar-mammarysyndrome, 181450 601622 Saethre-Chotzen syndrome, 101400 601623 Angelmansyndrome 601649 Blepharophimosis, epicanthus inversus, and ptosis, type2 601650 Paraganglioma, familial nonchromaffin, 2 601652 Glaucoma 1A,primary open angle, juvenile-onset, 137750 601653 Branchiootic syndrome601653 Branchiootorenal syndrome, 113650 601666 Insulin-dependentdiabetes mellitus-15 601669 Hirschsprung disease, one form 601676 Acuteinsulin response 601680 Distal arthrogryposis, type 2B 601682 Glaucoma1C, primary open angle 601687 Meesmann corneal dystrophy, 122100 601690Platelet-activating factor acetylhydrolase deficiency 601691 Retinitispigmentosa-19, 601718 601691 Stargardt disease-1, 248200 601691 Cone-roddystrophy 3 601691 Fundus flavimaculatus with macular dystrophy, 248200601692 Reis-Bucklers corneal dystrophy 601692 Corneal dystrophy,Avellino type 601692 Corneal dystrophy, Groenouw type I, 121900 601692Corneal dystrophy, lattice type I, 122200 601718 Retinitis pigmentosa-19601728 Bannayan-Zonana syndrome, 153480 601728 Cowden disease, 158350601728 Endometrial carcinoma 601728 Lhermitte-Duclos syndrome 601744Systemic lupus erythematosus, susceptibility to, 1 601757 Rhizomelicchondrodysplasia punctata, type 1, 215100 601768 Leukemia, acute myeloid601769 Osteoporosis, involutional 601769 Rickets, vitamin D-resistant,277440 601771 Glaucoma 3A, primary infantile, 231300 601777 Conedystrophy, progressive 601780 Ceroid-lipofuscinosis, neuronal-6, variantlate infantile 601785 Carbohydrate-deficient glycoprotein syndrome, typeI, 212065 601800 [Hair color, brown] 601843 Hypothyroidism, congenital,274400 601844 Pseudohypoaldosteronism type II 601846 Muscular dystrophywith rimmed vacuoles 601847 Progressive intrahepatic cholestasis-2601850 Retinitis pigmentosa-deafness syndrome 601863 Bare lymphocytesyndrome, complementation group C 601868 Deafness, autosomal dominant 13601884 [High bone mass] 601889 Lymphoma, diffuse large cell 601916Pancreatic cancer 601928 Monilethrix, 158000 601941 Insulin-dependentdiabetes mellitus-6 601954 Muscular dystrophy, limb-girdle, type 2G601969 Medulloblastoma, 155255 601969 Glioblastoma multiforme, 137800601975 Ectodermal dysplasia/skin fragility syndrome 601990 Neuroblastoma602014 Hypomagnesemia with secondary hypocalcemia 602023 Barttersyndrome, type 3 602025 Obesity/hyperinsulinism, susceptibility to602028 Multiple myeloma 602066 Convulsions, infantile and paroxysmalchoreoathetosis 602067 Cardiomyopathy, dilated, 1F 602078 Fibrosis ofextraocular muscles, congenital, 2 602080 Paget disease of bone-2 602081Speech-language disorder-1 602082 Corneal dystrophy, Thiel-Behnke type602084 Endometrial carcinoma 602085 Postaxial polydactyly, type A2602086 Arrhythmogenic right ventricular dysplasia-3 602087Arrhythmogenic right ventricular dysplasia-4 602088 Nephronophthisis,infantile 602089 Hemangioma, capillary, hereditary 602091 Marfansyndrome, atypical 602092 Deafness, autosomal recessive 18 602094Lipodystrophy, familial partial 602096 Alzheimer disease-5 602099Amytrophic lateral sclerosis-5 602116 Glioma 602117 Prader-Willisyndrome 602121 Deafness, autosomal dominant nonsyndromic sensorineural,1, 124900 602134 Tremor, familial essential, 2 602136 Refsum disease,infantile, 266510 602136 Zellweger syndrome-1, 214100 602136Adrenoleukodystrophy, neonatal, 202370 602153 Monilethrix, 158000 602216Peutz-Jeghers syndrome, 175200 602225 Cone-rod retinal dystrophy-2,120970 602225 Leber congenital amaurosis, type III 602235 Epilepsy,benign, neonatal, type 1, 121200 602279 Oculopharyngeal musculardystorphy, 164300 602279 Oculopharyngeal muscular dystrophy, autosomalrecessive, 257950 602280 Retinitis pigmentosa-14, 600132 602363Ellis-van Creveld-like syndrome 602397 Cholestasis, benign recurrentintrahepatic, 243300 602397 Cholestasis, progressive familialintrahepatic-1, 211600 602403 Alzheimer disease, susceptibility to602404 Parkinson disease, type 3 602447 Coronary artery disease,susceptibility to 602460 Deafness, autosomal dominant 15, 602459 602475Ossification of posterior longitudinal ligament of spine 602476 Febrileconvulsions, familial, 1 602477 Febrile convulsions, familial, 2 602491Hyperlipidemia, familial combined, 1 602522 Bartter syndrome, infantile,with sensorineural deafness 602544 Parkinson disease, juvenile, type 2,600116 602568 Homocystinuria-megaloblastic anemia, cbl E type, 236270602574 Deafness, autosomal dominant 12, 601842 602574 Deafness,autosomal dominant 8, 601543 602575 Nail-patella syndrome withopen-angle glaucoma, 137750 602575 Nail-patella syndrome, 161200 602616Carbohydrate-deficient glycoprotein syndrome, type II, 212066 602629Dystonia-6, torsion 602631 Rhabdomyosarcoma, 268210 602631 Breast Cancer602669 Anterior segment mesenchymal dysgenesis and cataract, 107250602669 Cataract, congenital 602685 Mental retardation, severe, withspasticity and tapetoretinal degeneration 602716 Nephrosis-1,congenital, Finnish type, 256300 602759 Prostate cancer, hereditary, 2,176807 602771 Muscular dystrophy, congenital, with early spine rigidity602772 Retinitis pitmentosa-24 602782 Faisalabad histiocytosis 602783Spastic paraplegia-7Mature Polypeptides

The present invention also encompasses mature forms of a polypeptidehaving the amino acid sequence of SEQ ID NO:Y and/or the amino acidsequence encoded by the cDNA in a deposited clone. Polynucleotidesencoding the mature forms (such as, for example, the polynucleotidesequence in SEQ ID NO:X and/or the polynucleotide sequence contained inthe cDNA of a deposited clone) are also encompassed by the invention.Moreover, fragments or variants of these polypeptides (such as,fragments as described herein, polypeptides at least 80%, 85%, 90%, 95%,96%, 97%, 98%, 99%, or 100% identical to these polypeptides, orpolypeptides encoded by a polynucleotide that hybridizes under stringentconditions to the complementary strand of the polynucleotide encodingthese polypeptides) are also encompassed by the invention. In preferredembodiments, these fragments or variants retain one or more functionalactivities of the full-length or mature form of the polypeptide (e.g.,biological activity (such as, for example, activity in detecting,preventing, treating and/or indicated disorders), antigenicity (abilityto bind, or compete with a polypeptide of the invention for binding, toan anti-polypeptide of the invention antibody), immunogenicity (abilityto generate antibody which binds to a specific polypeptide of theinvention), ability to form multimers with polypeptides of theinvention, and ability to bind to a receptor or ligand for a polypeptideof the invention). Antibodies that bind the polypeptides of theinvention, and polynucleotides encoding these polypeptides are alsoencompassed by the invention.

According to the signal hypothesis, proteins secreted by mammalian cellshave a signal or secretary leader sequence which is cleaved from themature protein once export of the growing protein chain across the roughendoplasmic reticulum has been initiated. Most mammalian cells and eveninsect cells cleave secreted proteins with the same specificity.However, in some cases, cleavage of a secreted protein is not entirelyuniform, which results in two or more mature species of the protein.Further, it has long been known that cleavage specificity of a secretedprotein is ultimately determined by the primary structure of thecomplete protein, that is, it is inherent in the amino acid sequence ofthe polypeptide.

Methods for predicting whether a protein has a signal sequence, as wellas the cleavage point for that sequence, are available. For instance,the method of McGeoch, Virus Res. 3:271-286 (1985), uses the informationfrom a short N-terminal charged region and a subsequent uncharged regionof the complete (uncleaved) protein. The method of von Heinje, NucleicAcids Res. 14:4683-4690 (1986) uses the information from the residuessurrounding the cleavage site, typically residues −13 to +2, where +1indicates the amino terminus of the secreted protein. The accuracy ofpredicting the cleavage points of known mammalian secretory proteins foreach of these methods is in the range of 75-80%. (von Heinje, supra.)However, the two methods do not always produce the same predictedcleavage point(s) for a given protein.

In the present case, the deduced amino acid sequence of the secretedpolypeptide was analyzed by a computer program called SignalP (HenrikNielsen et al., Protein Engineering 10:1-6 (1997)), which predicts thecellular location of a protein based on the amino acid sequence. As partof this computational prediction of localization, the methods of McGeochand von Heinje are incorporated. The analysis of the amino acidsequences of the secreted proteins described herein by this programprovided the results shown in Table 1A.

In specific embodiments, polypeptides of the invention comprise, oralternatively consist of, the predicted mature form of the polypeptideas delineated in columns 14 and 15 of Table 1A. Moreover, fragments orvariants of these polypeptides (such as, fragments as described herein,polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%identical to these polypeptides, or polypeptides encoded by apolynucleotide that hybridizes under stringent conditions to thecomplementary strand of the polynucleotide encoding these polypeptides)are also encompassed by the invention. In preferred embodiments, thesefragments or variants retain one or more functional activities of thefull-length or mature form of the polypeptide (e.g., biologicalactivity, antigenicity [ability to bind (or compete with a polypeptideof the invention for binding) to an anti-polypeptide of the inventionantibody], immunogenicity (ability to generate antibody which binds to aspecific polypeptide of the invention), ability to form multimers withpolypeptides of the invention, and ability to bind to a receptor orligand for a polypeptide of the invention). Antibodies that bind thepolypeptides of the invention, and polynucleotides encoding thesepolypeptides are also encompassed by the invention.

Polynucleotides encoding proteins comprising, or consisting of, thepredicted mature form of polypeptides of the invention (e.g.,polynucleotides having the sequence of SEQ ID NO: X (Table 1A, column4), the sequence delineated in columns 7 and 8 of Table 1A, and asequence encoding the mature polypeptide delineated in columns 14 and 15of Table 1A (e.g., the sequence of SEQ ID NO:X encoding the maturepolypeptide delineated in columns 14 and 15 of Table 1)) are alsoencompassed by the invention, as are fragments or variants of thesepolynucleotides (such as, fragments as described herein, polynucleotidesat least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical tothese polynucleotides, and nucleic acids which hybridizes understringent conditions to the complementary strand of the polynucleotide).

As one of ordinary skill would appreciate, however, cleavage sitessometimes vary from organism to organism and cannot be predicted withabsolute certainty. Accordingly, the present invention provides secretedpolypeptides having a sequence shown in SEQ ID NO:Y which have anN-terminus beginning within 15 residues of the predicted cleavage point(i.e., having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 moreor less contiguous residues of SEQ ID NO:Y at the N-terminus whencompared to the predicted mature form of the polypeptide (e.g., themature polypeptide delineated in columns 14 and 15 of Table 1).Similarly, it is also recognized that in some cases, cleavage of thesignal sequence from a secreted protein is not entirely uniform,resulting in more than one secreted species. These polypeptides, and thepolynucleotides encoding such polypeptides, are contemplated by thepresent invention.

Moreover, the signal sequence identified by the above analysis may notnecessarily predict the naturally occurring signal sequence. Forexample, the naturally occurring signal sequence may be further upstreamfrom the predicted signal sequence. However, it is likely that thepredicted signal sequence will be capable of directing the secretedprotein to the ER. Nonetheless, the present invention provides themature protein produced by expression of the polynucleotide sequence ofSEQ ID NO:X and/or the polynucleotide sequence contained in the cDNA ofa deposited clone, in a mammalian cell (e.g., COS cells, as describedbelow). These polypeptides, and the polynucleotides encoding suchpolypeptides, are contemplated by the present invention.

Polynucleotide and Polypeptide Variants

The present invention is also directed to variants of the polynucleotidesequence disclosed in SEQ ID NO:X or the complementary strand thereto,nucleotide sequences encoding the polypeptide of SEQ ID NO:Y, thenucleotide sequence of SEQ ID NO:X that encodes the polypeptide sequenceas defined in columns 13 and 14 of Table 1A, nucleotide sequencesencoding the polypeptide sequence as defined in columns 13 and 14 ofTable 1A, the nucleotide sequence of SEQ ID NO:X encoding thepolypeptide sequence as defined in column 5 of Table 1B.1, nucleotidesequences encoding the polypeptide as defined in column 6 and column 7of Table 1B.1, the nucleotide sequence as defined in columns 8 and 9 ofTable 2, nucleotide sequences encoding the polypeptide encoded by thenucleotide sequence as defined in columns 8 and 9 of Table 2, thenucleotide sequence as defined in column 6 of Table 1C, nucleotidesequences encoding the polypeptide encoded by the nucleotide sequence asdefined in column 6 of Table 1C, the cDNA sequence contained in ATCCDeposit NO: Z, nucleotide sequences encoding the polypeptide encoded bythe cDNA sequence contained in ATCC Deposit NO: Z, and/or nucleotidesequences encoding a mature (secreted) polypeptide encoded by the cDNAsequence contained in ATCC Deposit NO: Z.

The present invention also encompasses variants of the polypeptidesequence disclosed in SEQ ID NO:Y, the polypeptide as defined in columns13 and 14 of Table 1A, the polypeptide sequence as defined in columns 6and 7 of Table 1B.1, a polypeptide sequence encoded by the nucleotidesequence as defined in columns 8 and 9 of Table 2, a polypeptidesequence encoded by the nucleotide sequence as defined in column 6 ofTable 1C, a polypeptide sequence encoded by the complement of thepolynucleotide sequence in SEQ ID NO:X, the polypeptide sequence encodedby the cDNA sequence contained in ATCC Deposit NO: Z and/or a mature(secreted) polypeptide encoded by the cDNA sequence contained in ATCCDeposit NO: Z.

“Variant” refers to a polynucleotide or polypeptide differing from thepolynucleotide or polypeptide of the present invention, but retainingessential properties thereof. Generally, variants are overall closelysimilar, and, in many regions, identical to the polynucleotide orpolypeptide of the present invention.

Thus, one aspect of the invention provides an isolated nucleic acidmolecule comprising, or alternatively consisting of, a polynucleotidehaving a nucleotide sequence selected from the group consisting of: (a)a nucleotide sequence described in SEQ ID NO:X or contained in the cDNAsequence of ATCC Deposit No: Z; (b) a nucleotide sequence in SEQ ID NO:Xor the cDNA in ATCC Deposit No: Z which encodes the complete amino acidsequence of SEQ ID NO:Y or the complete amino acid sequence encoded bythe cDNA in ATCC Deposit No: Z; (c) a nucleotide sequence in SEQ ID NO:Xor the cDNA in ATCC Deposit No: Z which encodes a mature polypeptide(i.e., a secreted polypeptide (e.g., as delineated in columns 14 and 15of Table 1A)); (d) a nucleotide sequence in SEQ ID NO:X or the cDNAsequence of ATCC Deposit No: Z, which encodes a biologically activefragment of a polypeptide; (e) a nucleotide sequence in SEQ ID NO:X orthe cDNA sequence of ATCC Deposit No: Z, which encodes an antigenicfragment of a polypeptide; (f) a nucleotide sequence encoding apolypeptide comprising the complete amino acid sequence of SEQ ID NO:Yor the complete amino acid sequence encoded by the cDNA in ATCC DepositNo: Z; (g) a nucleotide sequence encoding a mature polypeptide of theamino acid sequence of SEQ ID NO:Y (i.e., a secreted polypeptide (e.g.,as delineated in columns 14 and 15 of Table 1A)) or a mature polypeptideof the amino acid sequence encoded by the cDNA in ATCC Deposit No: Z;(h) a nucleotide sequence encoding a biologically active fragment of apolypeptide having the complete amino acid sequence of SEQ ID NO:Y orthe complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; (i) a nucleotide sequence encoding an antigenic fragment of apolypeptide having the complete amino acid sequence of SEQ ID NO:Y orthe complete amino acid sequence encoded by the cDNA in ATCC Deposit No:Z; and (j) a nucleotide sequence complementary to any of the nucleotidesequences in (a), (b), (c), (d), (e), (f), (g), (h), or (i) above.

The present invention is also directed to nucleic acid molecules whichcomprise, or alternatively consist of, a nucleotide sequence which is atleast 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, forexample, any of the nucleotide sequences in (a), (b), (c), (d), (e),(f), (g), (h), (i), or (j) above, the nucleotide coding sequence in SEQID NO:X or the complementary strand thereto, the nucleotide codingsequence of the cDNA contained in ATCC Deposit No: Z or thecomplementary strand thereto, a nucleotide sequence encoding thepolypeptide of SEQ ID NO:Y, a nucleotide sequence encoding a polypeptidesequence encoded by the nucleotide sequence in SEQ ID NO:X, apolypeptide sequence encoded by the complement of the polynucleotidesequence in SEQ ID NO:X, a nucleotide sequence encoding the polypeptideencoded by the cDNA contained in ATCC Deposit No: Z, the nucleotidecoding sequence in SEQ ID NO:X as defined in columns 8 and 9 of Table 2or the complementary strand thereto, a nucleotide sequence encoding thepolypeptide encoded by the nucleotide sequence in SEQ ID NO:X as definedin columns 8 and 9 of Table 2 or the complementary strand thereto, thenucleotide coding sequence in SEQ ID NO:B as defined in column 6 ofTable 1C or the complementary strand thereto, a nucleotide sequenceencoding the polypeptide encoded by the nucleotide sequence in SEQ IDNO:B as defined in column 6 of Table 1C or the complementary strandthereto, the nucleotide sequence in SEQ ID NO:X encoding the polypeptidesequence as defined in columns 6 and 7 of Table 1B.1 or thecomplementary strand thereto, nucleotide sequences encoding thepolypeptide as defined in column 6 and 7 of Table 1B.1 or thecomplementary strand thereto, and/or polynucleotide fragments of any ofthese nucleic acid molecules (e.g., those fragments described herein).Polynucleotides which hybridize to the complement of these nucleic acidmolecules under stringent hybridization conditions or alternatively,under lower stringency conditions, are also encompassed by theinvention, as are polypeptides encoded by these polynucleotides andnucleic acids.

In a preferred embodiment, the invention encompasses nucleic acidmolecules which comprise, or alternatively, consist of a polynucleotidewhich hybridizes under stringent hybridization conditions, oralternatively, under lower stringency conditions, to a polynucleotide in(a), (b), (c), (d), (e), (f), (g), (h), or (i), above, as arepolypeptides encoded by these polynucleotides. In another preferredembodiment, polynucleotides which hybridize to the complement of thesenucleic acid molecules under stringent hybridization conditions, oralternatively, under lower stringency conditions, are also encompassedby the invention, as are polypeptides encoded by these polynucleotides.

In another embodiment, the invention provides a purified proteincomprising, or alternatively consisting of, a polypeptide having anamino acid sequence selected from the group consisting of: (a) thecomplete amino acid sequence of SEQ ID NO:Y or the complete amino acidsequence encoded by the cDNA in ATCC Deposit No: Z; (b) the amino acidsequence of a mature (secreted) form of a polypeptide having the aminoacid sequence of SEQ ID NO:Y (e.g., as delineated in columns 14 and 15of Table 1A) or a mature form of the amino acid sequence encoded by thecDNA in ATCC Deposit No: Z mature; (c) the amino acid sequence of abiologically active fragment of a polypeptide having the complete aminoacid sequence of SEQ ID NO:Y or the complete amino acid sequence encodedby the cDNA in ATCC Deposit No: Z; and (d) the amino acid sequence of anantigenic fragment of a polypeptide having the complete amino acidsequence of SEQ ID NO:Y or the complete amino acid sequence encoded bythe cDNA in ATCC Deposit No: Z.

The present invention is also directed to proteins which comprise, oralternatively consist of, an amino acid sequence which is at least 80%,85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example,any of the amino acid sequences in (a), (b), (c), or (d), above, theamino acid sequence shown in SEQ ID NO:Y, the amino acid sequenceencoded by the cDNA contained in ATCC Deposit No: Z, the amino acidsequence of the polypeptide encoded by the nucleotide sequence in SEQ IDNO:X as defined in columns 8 and 9 of Table 2, the amino acid sequenceof the polypeptide encoded by the nucleotide sequence in SEQ ID NO:B asdefined in column 6 of Table 1C, the amino acid sequence as defined incolumn 6 and 7 of Table 1B. 1, an amino acid sequence encoded by thenucleotide sequence in SEQ ID NO:X, and an amino acid sequence encodedby the complement of the polynucleotide sequence in SEQ ID NO:X.Fragments of these polypeptides are also provided (e.g., those fragmentsdescribed herein). Further proteins encoded by polynucleotides whichhybridize to the complement of the nucleic acid molecules encoding theseamino acid sequences under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention, as are the polynucleotides encoding these proteins.

By a nucleic acid having a nucleotide sequence at least, for example,95% “identical” to a reference nucleotide sequence of the presentinvention, it is intended that the nucleotide sequence of the nucleicacid is identical to the reference sequence except that the nucleotidesequence may include up to five point mutations per each 100 nucleotidesof the reference nucleotide sequence encoding the polypeptide. In otherwords, to obtain a nucleic acid having a nucleotide sequence at least95% identical to a reference nucleotide sequence, up to 5% of thenucleotides in the reference sequence may be deleted or substituted withanother nucleotide, or a number of nucleotides up to 5% of the totalnucleotides in the reference sequence may be inserted into the referencesequence. The query sequence may be an entire sequence referred to inTable 1B or 2 as the ORF (open reading frame), or any fragment specifiedas described herein.

As a practical matter, whether any particular nucleic acid molecule orpolypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%identical to a nucleotide sequence of the present invention can bedetermined conventionally using known computer programs. A preferredmethod for determining the best overall match between a query sequence(a sequence of the present invention) and a subject sequence, alsoreferred to as a global sequence alignment, can be determined using theFASTDB computer program based on the algorithm of Brutlag et al. (Comp.App. Biosci. 6:237-245 (1990)). In a sequence alignment the query andsubject sequences are both DNA sequences. An RNA sequence can becompared by converting U's to T's. The result of said global sequencealignment is expressed as percent identity. Preferred parameters used ina FASTDB alignment of DNA sequences to calculate percent identity are:Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30,Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap SizePenalty 0.05, Window Size=500 or the length of the subject nucleotidesequence, whichever is shorter.

If the subject sequence is shorter than the query sequence because of 5′or 3′ deletions, not because of internal deletions, a manual correctionmust be made to the results. This is because the FASTDB program does notaccount for 5′ and 3′ truncations of the subject sequence whencalculating percent identity. For subject sequences truncated at the 5′or 3′ ends, relative to the query sequence, the percent identity iscorrected by calculating the number of bases of the query sequence thatare 5′ and 3′ of the subject sequence, which are not matched/aligned, asa percent of the total bases of the query sequence. Whether a nucleotideis matched/aligned is determined by results of the FASTDB sequencealignment. This percentage is then subtracted from the percent identity,calculated by the above FASTDB program using the specified parameters,to arrive at a final percent identity score. This corrected score iswhat is used for the purposes of the present invention. Only basesoutside the 5′ and 3′ bases of the subject sequence, as displayed by theFASTDB alignment, which are not matched/aligned with the query sequence,are calculated for the purposes of manually adjusting the percentidentity score.

For example, a 90 base subject sequence is aligned to a 100 base querysequence to determine percent identity. The deletions occur at the 5′end of the subject sequence and therefore, the FASTDB alignment does notshow a matched/alignment of the first 10 bases at 5′ end. The 10unpaired bases represent 10% of the sequence (number of bases at the 5′and 3′ ends not matched/total number of bases in the query sequence) so10% is subtracted from the percent identity score calculated by theFASTDB program. If the remaining 90 bases were perfectly matched thefinal percent identity would be 90%. In another example, a 90 basesubject sequence is compared with a 100 base query sequence. This timethe deletions are internal deletions so that there are no bases on the5′ or 3′ of the subject sequence which are not matched/aligned with thequery. In this case the percent identity calculated by FASTDB is notmanually corrected. Once again, only bases 5′ and 3′ of the subjectsequence which are not matched/aligned with the query sequence aremanually corrected for. No other manual corrections are to be made forthe purposes of the present invention.

By a polypeptide having an amino acid sequence at least, for example,95% “identical” to a query amino acid sequence of the present invention,it is intended that the amino acid sequence of the subject polypeptideis identical to the query sequence except that the subject polypeptidesequence may include up to five amino acid alterations per each 100amino acids of the query amino acid sequence. In other words, to obtaina polypeptide having an amino acid sequence at least 95% identical to aquery amino acid sequence, up to 5% of the amino acid residues in thesubject sequence may be inserted, deleted, (indels) or substituted withanother amino acid. These alterations of the reference sequence mayoccur at the amino or carboxy terminal positions of the reference aminoacid sequence or anywhere between those terminal positions, interspersedeither individually among residues in the reference sequence or in oneor more contiguous groups within the reference sequence.

As a practical matter, whether any particular polypeptide is at least80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, theamino acid sequence of a polypeptide referred to in Table 1A (e.g., theamino acid sequence delineated in columns 14 and 15) or a fragmentthereof, Table 1B.1 (e.g., the amino acid sequence identified in column6) or a fragment thereof, Table 2 (e.g., the amino acid sequence of thepolypeptide encoded by the polynucleotide sequence defined in columns 8and 9 of Table 2) or a fragment thereof, the amino acid sequence of thepolypeptide encoded by the polynucleotide sequence in SEQ ID NO:B asdefined in column 6 of Table 1C or a fragment thereof, the amino acidsequence of the polypeptide encoded by the nucleotide sequence in SEQ IDNO:X or a fragment thereof, or the amino acid sequence of thepolypeptide encoded by cDNA contained in ATCC Deposit No: Z, or afragment thereof, the amino acid sequence of a mature (secreted)polypeptide encoded by cDNA contained in ATCC Deposit No: Z, or afragment thereof, can be determined conventionally using known computerprograms. A preferred method for determining the best overall matchbetween a query sequence (a sequence of the present invention) and asubject sequence, also referred to as a global sequence alignment, canbe determined using the FASTDB computer program based on the algorithmof Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)). In a sequencealignment the query and subject sequences are either both nucleotidesequences or both amino acid sequences. The result of said globalsequence alignment is expressed as percent identity. Preferredparameters used in a FASTDB amino acid alignment are: Matrix=PAM 0,k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization GroupLength=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5,Gap Size Penalty=0.05, Window Size=500 or the length of the subjectamino acid sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence due to N- orC-terminal deletions, not because of internal deletions, a manualcorrection must be made to the results. This is because the FASTDBprogram does not account for N- and C-terminal truncations of thesubject sequence when calculating global percent identity. For subjectsequences truncated at the N- and C-termini, relative to the querysequence, the percent identity is corrected by calculating the number ofresidues of the query sequence that are N- and C-terminal of the subjectsequence, which are not matched/aligned with a corresponding subjectresidue, as a percent of the total bases of the query sequence. Whethera residue is matched/aligned is determined by results of the FASTDBsequence alignment. This percentage is then subtracted from the percentidentity, calculated by the above FASTDB program using the specifiedparameters, to arrive at a final percent identity score. This finalpercent identity score is what is used for the purposes of the presentinvention. Only residues to the N- and C-termini of the subjectsequence, which are not matched/aligned with the query sequence, areconsidered for the purposes of manually adjusting the percent identityscore. That is, only query residue positions outside the farthest N- andC-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a100 residue query sequence to determine percent identity. The deletionoccurs at the N-terminus of the subject sequence and therefore, theFASTDB alignment does not show a matching/alignment of the first 10residues at the N-terminus. The 10 unpaired residues represent 10% ofthe sequence (number of residues at the N- and C-termini notmatched/total number of residues in the query sequence) so 10% issubtracted from the percent identity score calculated by the FASTDBprogram. If the remaining 90 residues were perfectly matched the finalpercent identity would be 90%. In another example, a 90 residue subjectsequence is compared with a 100 residue query sequence. This time thedeletions are internal deletions so there are no residues at the N- orC-termini of the subject sequence which are not matched/aligned with thequery. In this case the percent identity calculated by FASTDB is notmanually corrected. Once again, only residue positions outside the N-and C-terminal ends of the subject sequence, as displayed in the FASTDBalignment, which are not matched/aligned with the query sequnce aremanually corrected for. No other manual corrections are to made for thepurposes of the present invention.

The polynucleotide variants of the invention may contain alterations inthe coding regions, non-coding regions, or both. Especially preferredare polynucleotide variants containing alterations which produce silentsubstitutions, additions, or deletions, but do not alter the propertiesor activities of the encoded polypeptide. Nucleotide variants producedby silent substitutions due to the degeneracy of the genetic code arepreferred. Moreover, polypeptide variants in which less than 50, lessthan 40, less than 30, less than 20, less than 10, or 5-50, 5-25, 5-10,1-5, or 1-2 amino acids are substituted, deleted, or added in anycombination are also preferred. Polynucleotide variants can be producedfor a variety of reasons, e.g., to optimize codon expression for aparticular host (change codons in the human mRNA to those preferred by abacterial host such as E. coli).

Naturally occurring variants are called “allelic variants,” and refer toone of several alternate forms of a gene occupying a given locus on achromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons,New York (1985)). These allelic variants can vary at either thepolynucleotide and/or polypeptide level and are included in the presentinvention. Alternatively, non-naturally occurring variants may beproduced by mutagenesis techniques or by direct synthesis.

Using known methods of protein engineering and recombinant DNAtechnology, variants may be generated to improve or alter thecharacteristics of the polypeptides of the present invention. Forinstance, one or more amino acids can be deleted from the N-terminus orC-terminus of the polypeptide of the present invention withoutsubstantial loss of biological function. As an example, Ron et al. (J.Biol. Chem. 268: 2984-2988 (1993)) reported variant KGF proteins havingheparin binding activity even after deleting 3, 8, or 27 amino-terminalamino acid residues. Similarly, Interferon gamma exhibited up to tentimes higher activity after deleting 8-10 amino acid residues from thecarboxy terminus of this protein. (Dobeli et al., J. Biotechnology7:199-216 (1988).)

Moreover, ample evidence demonstrates that variants often retain abiological activity similar to that of the naturally occurring protein.For example, Gayle and coworkers (J. Biol. Chem. 268:22105-22111 (1993))conducted extensive mutational analysis of human cytokine IL-1a. Theyused random mutagenesis to generate over 3,500 individual IL-1a mutantsthat averaged 2.5 amino acid changes per variant over the entire lengthof the molecule. Multiple mutations were examined at every possibleamino acid position. The investigators found that “[m]ost of themolecule could be altered with little effect on either [binding orbiological activity].” In fact, only 23 unique amino acid sequences, outof more than 3,500 nucleotide sequences examined, produced a proteinthat significantly differed in activity from wild-type.

Furthermore, even if deleting one or more amino acids from theN-terminus or C-terminus of a polypeptide results in modification orloss of one or more biological functions, other biological activitiesmay still be retained. For example, the ability of a deletion variant toinduce and/or to bind antibodies which recognize the secreted form willlikely be retained when less than the majority of the residues of thesecreted form are removed from the N-terminus or C-terminus. Whether aparticular polypeptide lacking N- or C-terminal residues of a proteinretains such immunogenic activities can readily be determined by routinemethods described herein and otherwise known in the art.

Thus, the invention further includes polypeptide variants which show afunctional activity (e.g., biological activity) of the polypeptides ofthe invention. Such variants include deletions, insertions, inversions,repeats, and substitutions selected according to general rules known inthe art so as have little effect on activity.

The present application is directed to nucleic acid molecules at least80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleicacid sequences disclosed herein, (e.g., encoding a polypeptide havingthe amino acid sequence of an N and/or C terminal deletion),irrespective of whether they encode a polypeptide having functionalactivity. This is because even where a particular nucleic acid moleculedoes not encode a polypeptide having functional activity, one of skillin the art would still know how to use the nucleic acid molecule, forinstance, as a hybridization probe or a polymerase chain reaction (PCR)primer. Uses of the nucleic acid molecules of the present invention thatdo not encode a polypeptide having functional activity include, interalia, (1) isolating a gene or allelic or splice variants thereof in acDNA library; (2) in situ hybridization (e.g., “FISH”) to metaphasechromosomal spreads to provide precise chromosomal location of the gene,as described in Verma et al., Human Chromosomes: A Manual of BasicTechniques, Pergamon Press, New York (1988); (3) Northern Blot analysisfor detecting mRNA expression in specific tissues (e.g., normal ordiseased tissues); and (4) in situ hybridization (e.g., histochemistry)for detecting mRNA expression in specific tissues (e.g., normal ordiseased tissues).

Preferred, however, are nucleic acid molecules having sequences at least80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleicacid sequences disclosed herein, which do, in fact, encode a polypeptidehaving functional activity. By a polypeptide having “functionalactivity” is meant, a polypeptide capable of displaying one or moreknown functional activities associated with a full-length (complete)protein and/or a mature (secreted) protein of the invention. Suchfunctional activities include, but are not limited to, biologicalactivity, antigenicity [ability to bind (or compete with a polypeptideof the invention for binding) to an anti-polypeptide of the inventionantibody], immunogenicity (ability to generate antibody which binds to aspecific polypeptide of the invention), ability to form multimers withpolypeptides of the invention, and ability to bind to a receptor orligand for a polypeptide of the invention.

The functional activity of the polypeptides, and fragments, variants andderivatives of the invention, can be assayed by various methods.

For example, in one embodiment where one is assaying for the ability tobind or compete with a full-length polypeptide of the present inventionfor binding to an anti-polypeptide antibody, various immunoassays knownin the art can be used, including but not limited to, competitive andnon-competitive assay systems using techniques such asradioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich”immunoassays, immunoradiometric assays, gel diffusion precipitationreactions, immunodiffusion assays, in situ immunoassays (using colloidalgold, enzyme or radioisotope labels, for example), western blots,precipitation reactions, agglutination assays (e.g., gel agglutinationassays, hemagglutination assays), complement fixation assays,immunofluorescence assays, protein A assays, and immunoelectrophoresisassays, etc. In one embodiment, antibody binding is detected bydetecting a label on the primary antibody. In another embodiment, theprimary antibody is detected by detecting binding of a secondaryantibody or reagent to the primary antibody. In a further embodiment,the secondary antibody is labeled. Many means are known in the art fordetecting binding in an immunoassay and are within the scope of thepresent invention.

In another embodiment, where a ligand is identified, or the ability of apolypeptide fragment, variant or derivative of the invention tomultimerize is being evaluated, binding can be assayed, e.g., by meanswell-known in the art, such as, for example, reducing and non-reducinggel chromatography, protein affinity chromatography, and affinityblotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123(1995). In another embodiment, the ability of physiological correlatesof a polypeptide of the present invention to bind to a substrate(s) ofthe polypeptide of the invention can be routinely assayed usingtechniques known in the art.

In addition, assays described herein (see Examples) and otherwise knownin the art may routinely be applied to measure the ability of thepolypeptides of the present invention and fragments, variants andderivatives thereof to elicit polypeptide related biological activity(either in vitro or in vivo). Other methods will be known to the skilledartisan and are within the scope of the invention.

Of course, due to the degeneracy of the genetic code, one of ordinaryskill in the art will immediately recognize that a large number of thenucleic acid molecules having a sequence at least 80%, 85%, 90%, 95%,96%, 97%, 98%, 99%, or 100% identical to, for example, the nucleic acidsequence of the cDNA contained in ATCC Deposit No: Z, the nucleic acidsequence referred to in Table 1B (SEQ ID NO:X), the nucleic acidsequence disclosed in Table 1A (e.g., the nucleic acid sequencedelineated in columns 7 and 8), the nucleic acid sequence disclosed inTable 2 (e.g., the nucleic acid sequence delineated in columns 8 and 9)or fragments thereof, will encode polypeptides “having functionalactivity.” In fact, since degenerate variants of any of these nucleotidesequences all encode the same polypeptide, in many instances, this willbe clear to the skilled artisan even without performing the abovedescribed comparison assay. It will be further recognized in the artthat, for such nucleic acid molecules that are not degenerate variants,a reasonable number will also encode a polypeptide having functionalactivity. This is because the skilled artisan is fully aware of aminoacid substitutions that are either less likely or not likely tosignificantly effect protein function (e.g., replacing one aliphaticamino acid with a second aliphatic amino acid), as further describedbelow.

For example, guidance concerning how to make phenotypically silent aminoacid substitutions is provided in Bowie et al., “Deciphering the Messagein Protein Sequences: Tolerance to Amino Acid Substitutions,” Science247:1306-1310 (1990), wherein the authors indicate that there are twomain strategies for studying the tolerance of an amino acid sequence tochange.

The first strategy exploits the tolerance of amino acid substitutions bynatural selection during the process of evolution. By comparing aminoacid sequences in different species, conserved amino acids can beidentified. These conserved amino acids are likely important for proteinfunction. In contrast, the amino acid positions where substitutions havebeen tolerated by natural selection indicates that these positions arenot critical for protein function. Thus, positions tolerating amino acidsubstitution could be modified while still maintaining biologicalactivity of the protein.

The second strategy uses genetic engineering to introduce amino acidchanges at specific positions of a cloned gene to identify regionscritical for protein function. For example, site directed mutagenesis oralanine-scanning mutagenesis (introduction of single alanine mutationsat every residue in the molecule) can be used. See Cunningham and Wells,Science 244:1081-1085 (1989). The resulting mutant molecules can then betested for biological activity.

As the authors state, these two strategies have revealed that proteinsare surprisingly tolerant of amino acid substitutions. The authorsfurther indicate which amino acid changes are likely to be permissive atcertain amino acid positions in the protein. For example, most buried(within the tertiary structure of the protein) amino acid residuesrequire nonpolar side chains, whereas few features of surface sidechains are generally conserved. Moreover, tolerated conservative aminoacid substitutions involve replacement of the aliphatic or hydrophobicamino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residuesSer and Thr; replacement of the acidic residues Asp and Glu; replacementof the amide residues Asn and Gln, replacement of the basic residuesLys, Arg, and His; replacement of the aromatic residues Phe, Tyr, andTrp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met,and Gly.

Besides conservative amino acid substitution, variants of the presentinvention include (i) substitutions with one or more of thenon-conserved amino acid residues, where the substituted amino acidresidues may or may not be one encoded by the genetic code, or (ii)substitutions with one or more of the amino acid residues having asubstituent group, or (iii) fusion of the mature polypeptide withanother compound, such as a compound to increase the stability and/orsolubility of the polypeptide (for example, polyethylene glycol), (iv)fusion of the polypeptide with additional amino acids, such as, forexample, an IgG Fc fusion region peptide, serum albumin (preferablyhuman serum albumin) or a fragment thereof, or leader or secretorysequence, or a sequence facilitating purification, or (v) fusion of thepolypeptide with another compound, such as albumin (including but notlimited to recombinant albumin (see, e.g., U.S. Pat. No. 5,876,969,issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883,issued Jun. 16, 1998, herein incorporated by reference in theirentirety)). Such variant polypeptides are deemed to be within the scopeof those skilled in the art from the teachings herein.

For example, polypeptide variants containing amino acid substitutions ofcharged amino acids with other charged or neutral amino acids mayproduce proteins with improved characteristics, such as lessaggregation. Aggregation of pharmaceutical formulations both reducesactivity and increases clearance due to the aggregate's immunogenicactivity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967);Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev.Therapeutic Drug Carrier Systems 10:307-377 (1993).

A further embodiment of the invention relates to polypeptides whichcomprise the amino acid sequence of a polypeptide having an amino acidsequence which contains at least one amino acid substitution, but notmore than 50 amino acid substitutions, even more preferably, not morethan 40 amino acid substitutions, still more preferably, not more than30 amino acid substitutions, and still even more preferably, not morethan 20 amino acid substitutions from a polypeptide sequence disclosedherein. Of course it is highly preferable for a polypeptide to have anamino acid sequence which, for example, comprises the amino acidsequence of a polypeptide of SEQ ID NO:Y, the amino acid sequence of themature (e.g., secreted) polypeptide of SEQ ID NO:Y, an amino acidsequence encoded by SEQ ID NO:X, an amino acid sequence encoded by theportion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, anamino acid sequence encoded by the complement of SEQ ID NO:X, an aminoacid sequence encoded by cDNA contained in ATCC Deposit No: Z, and/orthe amino acid sequence of a mature (secreted) polypeptide encoded bycDNA contained in ATCC Deposit No: Z, or a fragment thereof, whichcontains, in order of ever-increasing preference, at least one, but notmore than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions.

In specific embodiments, the polypeptides of the invention comprise, oralternatively, consist of, fragments or variants of a reference aminoacid sequence selected from: (a) the amino acid sequence of SEQ ID NO:Yor fragments thereof (e.g., the mature formand/or other fragmentsdescribed herein); (b) the amino acid sequence encoded by SEQ ID NO:X orfragments thereof; (c) the amino acid sequence encoded by the complementof SEQ ID NO:X or fragments thereof; (d) the amino acid sequence encodedby the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2or fragments thereof; and (e) the amino acid sequence encoded by cDNAcontained in ATCC Deposit No: Z or fragments thereof; wherein thefragments or variants have 1-5, 5-10, 5-25, 5-50, 10-50 or 50-150, aminoacid residue additions, substitutions, and/or deletions when compared tothe reference amino acid sequence. In preferred embodiments, the aminoacid substitutions are conservative. Polynucleotides encoding thesepolypeptides are also encompassed by the invention.

Polynucleotide and Polypeptide Fragments

The present invention is also directed to polynucleotide fragments ofthe polynucleotides (nucleic acids) of the invention. In the presentinvention, a “polynucleotide fragment” refers to a polynucleotide havinga nucleic acid sequence which, for example: is a portion of the cDNAcontained in ATCC Deposit No: Z or the complementary strand thereto; isa portion of the polynucleotide sequence encoding the polypeptideencoded by the cDNA contained in ATCC Deposit No: Z or the complementarystrand thereto; is a portion of the polynucleotide sequence encoding themature (secreted) polypeptide encoded by the cDNA contained in ATCCDeposit No: Z or the complementary strand thereto; is a portion of apolynucleotide sequence encoding the mature amino acid sequence asdefined in columns 14 and 15 of Table 1A or the complementary strandthereto; is a portion of a polynucleotide sequence encoding the aminoacid sequence encoded by the region of SEQ ID NO:X as defined in columns8 and 9 of Table 2 or the complementary strand thereto; is a portion ofthe polynucleotide sequence of SEQ ID NO:X as defined in columns 8 and 9of Table 2 or the complementary strand thereto; is a portion of thepolynucleotide sequence in SEQ ID NO:X or the complementary strandthereto; is a polynucleotide sequence encoding a portion of thepolypeptide of SEQ ID NO:Y; is a polynucleotide sequence encoding aportion of a polypeptide encoded by SEQ ID NO:X; is a polynucleotidesequence encoding a portion of a polypeptide encoded by the complementof the polynucleotide sequence in SEQ ID NO:X; is a portion of apolynucleotide sequence encoding the amino acid sequence encoded by theregion of SEQ ID NO:B as defined in column 6 of Table 1C or thecomplementary strand thereto; or is a portion of the polynucleotidesequence of SEQ ID NO:B as defined in column 6 of Table 1C or thecomplementary strand thereto.

The polynucleotide fragments of the invention are preferably at leastabout 15 nt, and more preferably at least about 20 nt, still morepreferably at least about 30 nt, and even more preferably, at leastabout 40 nt, at least about 50 nt, at least about 75 nt, or at leastabout 150 nt in length. A fragment “at least 20 nt in length,” forexample, is intended to include 20 or more contiguous bases from thecDNA sequence contained in ATCC Deposit No: Z, or the nucleotidesequence shown in SEQ ID NO:X or the complementary stand thereto. Inthis context “about” includes the particularly recited value or a valuelarger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at eitherterminus or at both termini. These nucleotide fragments have uses thatinclude, but are not limited to, as diagnostic probes and primers asdiscussed herein. Of course, larger fragments (e.g., at least 160, 170,180, 190, 200, 250, 500, 600, 1000, or 2000 nucleotides in length) arealso encompassed by the invention.

Moreover, representative examples of polynucleotide fragments of theinvention comprise, or alternatively consist of, a sequence from aboutnucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300,301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700,701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050,1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350,1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650,1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950,1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250,2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550,2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850,2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150,3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450,3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750,3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050,4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350,4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650,4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950,4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250,5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550,5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850,5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150,6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450,6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750,6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050,7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the endof SEQ ID NO:X, or the complementary strand thereto. In this context“about” includes the particularly recited range or a range larger orsmaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus orat both termini. Preferably, these fragments encode a polypeptide whichhas a functional activity (e.g., biological activity). More preferably,these polynucleotides can be used as probes or primers as discussedherein. Polynucleotides which hybridize to one or more of thesepolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions are also encompassed bythe invention, as are polypeptides encoded by these polynucleotides.

Further representative examples of polynucleotide fragments of theinvention comprise, or alternatively consist of, a sequence from aboutnucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300,301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 601-650, 651-700,701-750, 751-800, 801-850, 851-900, 901-950, 951-1000, 1001-1050,1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350,1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650,1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950,1951-2000, 2001-2050, 2051-2100, 2101-2150, 2151-2200, 2201-2250,2251-2300, 2301-2350, 2351-2400, 2401-2450, 2451-2500, 2501-2550,2551-2600, 2601-2650, 2651-2700, 2701-2750, 2751-2800, 2801-2850,2851-2900, 2901-2950, 2951-3000, 3001-3050, 3051-3100, 3101-3150,3151-3200, 3201-3250, 3251-3300, 3301-3350, 3351-3400, 3401-3450,3451-3500, 3501-3550, 3551-3600, 3601-3650, 3651-3700, 3701-3750,3751-3800, 3801-3850, 3851-3900, 3901-3950, 3951-4000, 4001-4050,4051-4100, 4101-4150, 4151-4200, 4201-4250, 4251-4300, 4301-4350,4351-4400, 4401-4450, 4451-4500, 4501-4550, 4551-4600, 4601-4650,4651-4700, 4701-4750, 4751-4800, 4801-4850, 4851-4900, 4901-4950,4951-5000, 5001-5050, 5051-5100, 5101-5150, 5151-5200, 5201-5250,5251-5300, 5301-5350, 5351-5400, 5401-5450, 5451-5500, 5501-5550,5551-5600, 5601-5650, 5651-5700, 5701-5750, 5751-5800, 5801-5850,5851-5900, 5901-5950, 5951-6000, 6001-6050, 6051-6100, 6101-6150,6151-6200, 6201-6250, 6251-6300, 6301-6350, 6351-6400, 6401-6450,6451-6500, 6501-6550, 6551-6600, 6601-6650, 6651-6700, 6701-6750,6751-6800, 6801-6850, 6851-6900, 6901-6950, 6951-7000, 7001-7050,7051-7100, 7101-7150, 7151-7200, 7201-7250, 7251-7300 or 7301 to the endof the cDNA sequence contained in ATCC Deposit No: Z, or thecomplementary strand thereto. In this context “about” includes theparticularly recited range or a range larger or smaller by several (5,4, 3, 2, or 1) nucleotides, at either terminus or at both termini.Preferably, these fragments encode a polypeptide which has a functionalactivity (e.g., biological activity). More preferably, thesepolynucleotides can be used as probes or primers as discussed herein.Polynucleotides which hybridize to one or more of these polynucleotidesunder stringent hybridization conditions or alternatively, under lowerstringency conditions are also encompassed by the invention, as arepolypeptides encoded by these polynucleotides.

Moreover, representative examples of polynucleotide fragments of theinvention comprise, or alternatively consist of, a nucleic acid sequencecomprising one, two, three, four, five, six, seven, eight, nine, ten, ormore of the above described polynucleotide fragments of the invention incombination with a polynucleotide sequence delineated in Table 1C column6. Additional, representative examples of polynucleotide fragments ofthe invention comprise, or alternatively consist of, a nucleic acidsequence comprising one, two, three, four, five, six, seven, eight,nine, ten, or more of the above described polynucleotide fragments ofthe invention in combination with a polynucleotide sequence that is thecomplementary strand of a sequence delineated in column 6 of Table 1C.In further embodiments, the above-described polynucleotide fragments ofthe invention comprise, or alternatively consist of, sequencesdelineated in Table 1C, column 6, and have a nucleic acid sequence whichis different from that of the BAC fragment having the sequence disclosedin SEQ ID NO:B (see Table 1C, column 5). In additional embodiments, theabove-described polynucleotide fragments of the invention comprise, oralternatively consist of, sequences delineated in Table 1C, column 6,and have a nucleic acid sequence which is different from that publishedfor the BAC clone identified as BAC ID NO:A (see Table 1C, column 4). Inadditional embodiments, the above-described polynucleotides of theinvention comprise, or alternatively consist of, sequences delineatedTable 1C, column 6, and have a nucleic acid sequence which is differentfrom that contained in the BAC clone identified as BAC ID NO:A (seeTable 1C, column 4). Polypeptides encoded by these polynucleotides,other polynucleotides that encode these polypeptides, and antibodiesthat bind these polypeptides are also encompassed by the invention.Additionally, fragments and variants of the above-describedpolynucleotides and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more fragments of the sequences delineatedin column 6 of Table 1C, and the polynucleotide sequence of SEQ ID NO:X(e.g., as defined in Table 1C, column 2) or fragments or variantsthereof. Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more fragments of the sequences delineatedin column 6 of Table 1C which correspond to the same ATCC Deposit No: Z(see Table 1C, column 1), and the polynucleotide sequence of SEQ ID NO:X(e.g., as defined in Table 1A, 1B, or 1C) or fragments or variantsthereof. Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of, one, two, three, four, five, six,seven, eight, nine, ten, or more fragments of the sequences delineatedin the same row of column 6 of Table 1C, and the polynucleotide sequenceof SEQ ID NO:X (e.g., as defined in Table 1A, 1B, or 1C) or fragments orvariants thereof. Polypeptides encoded by these polynucleotides, otherpolynucleotides that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of one of the sequences delineated in column 6of Table 1C and the 5′ 10 polynucleotides of the sequence of SEQ ID NO:Xare directly contiguous. Nucleic acids which hybridize to the complementof these 20 contiguous polynucleotides under stringent hybridizationconditions or alternatively, under lower stringency conditions, are alsoencompassed by the invention. Polypeptides encoded by thesepolynucleotides and/or nucleic acids, other polynucleotides and/ornucleic acids that encode these polypeptides, and antibodies that bindthese polypeptides are also encompassed by the invention. Additionally,fragments and variants of the above-described polynucleotides, nucleicacids, and polypeptides are also encompassed by the invention.

In additional specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of one of the sequences delineated in column 6of Table 1C and the 5′ 10 polynucleotides of a fragment or variant ofthe sequence of SEQ ID NO:X (e.g., as described herein) are directlycontiguous Nucleic acids which hybridize to the complement of these 20contiguous polynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

In further specific embodiments, polynucleotides of the inventioncomprise, or alternatively consist of a polynucleotide sequence in whichthe 3′ 10 polynucleotides of a fragment or variant of the sequence ofSEQ ID NO:X and the 5′ 10 polynucleotides of the sequence of one of thesequences delineated in column 6 of Table 1C are directly contiguous.Nucleic acids which hybridize to the complement of these 20 contiguouspolynucleotides under stringent hybridization conditions oralternatively, under lower stringency conditions, are also encompassedby the invention. Polypeptides encoded by these polynucleotides and/ornucleic acids, other polynucleotides and/or nucleic acids encoding thesepolypeptides, and antibodies that bind these polypeptides are alsoencompassed by the invention. Additionally, fragments and variants ofthe above-described polynucleotides, nucleic acids, and polypeptides arealso encompassed by the invention.

In specific embodiments, polynucleotides of the invention comprise, oralternatively consist of a polynucleotide sequence in which the 3′ 10polynucleotides of one of the sequences delineated in column 6 of Table1C and the 5′ 10 polynucleotides of another sequence in column 6 aredirectly contiguous. In preferred embodiments, the 3′ 10 polynucleotidesof one of the sequences delineated in column 6 of Table 1C is directlycontiguous with the 5′ 10 polynucleotides of the next sequential exondelineated in Table 1C, column 6. Nucleic acids which hybridize to thecomplement of these 20 contiguous polynucleotides under stringenthybridization conditions or alternatively, under lower stringencyconditions, are also encompassed by the invention. Polypeptides encodedby these polynucleotides and/or nucleic acids, other polynucleotidesand/or nucleic acids encoding these polypeptides, and antibodies thatbind these polypeptides are also encompassed by the invention.Additionally, fragments and variants of the above-describedpolynucleotides, nucleic acids, and polypeptides are also encompassed bythe invention.

In the present invention, a “polypeptide fragment” refers to an aminoacid sequence which is a portion of the amino acid sequence contained inSEQ ID NO:Y, is a portion of the mature form of SEQ ID NO:Y as definedin columns 14 and 15 of Table 1A, a portion of an amino acid sequenceencoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 ofTable 2, is a portion of an amino acid sequence encoded by thepolynucleotide sequence of SEQ ID NO:X, is a portion of an amino acidsequence encoded by the complement of the polynucleotide sequence in SEQID NO:X, is a portion of the amino acid sequence of a mature (secreted)polypeptide encoded by the cDNA contained in ATCC Deposit No: Z, and/oris a portion of an amino acid sequence encoded by the cDNA contained inATCC Deposit No: Z. Protein (polypeptide) fragments may be“free-standing,” or comprised within a larger polypeptide of which thefragment forms a part or region, most preferably as a single continuousregion. Representative examples of polypeptide fragments of theinvention, include, for example, fragments comprising, or alternativelyconsisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80,81-100, 101-120, 121-140, 141-160, 161-180, 181-200, 201-220, 221-240,241-260, 261-280, 281-300, 301-320, 321-340, 341-360, 361-380, 381-400,401-420, 421-440, 441-460, 461-480, 481-500, 501-520, 521-540, 541-560,561-580, 581-600, 601-620, 621-640, 641-660, 661-680, 681-700, 701-720,721-740, 741-760, 761-780, 781-800, 801-820, 821-840, 841-860, 861-880,881-900, 901-920, 921-940, 941-960, 961-980, 981-1000, 1001-1020,1021-1040, 1041-1060, 1061-1080, 1081-1100, 1101-1120, 1121-1140,1141-1160, 1161-1180, 1181-1200, 1201-1220, 1221-1240, 1241-1260,1261-1280, 1281-1300, 1301-1320, 1321-1340, 1341-1360, 1361-1380,1381-1400, 1401-1420, 1421-1440, or 1441 to the end of the coding regionof cDNA and SEQ ID NO: Y. In a preferred embodiment, polypeptidefragments of the invention include, for example, fragments comprising,or alternatively consisting of, from about amino acid number 1-20,21-40, 41-60, 61-80, 81-100, 101-120, 121-140, 141-160, 161-180,181-200, 201-220, 221-240, 241-260, 261-280, 281-300, 301-320, 321-340,341-360, 361-380, 381-400, 401-420, 421-440, 441-460, 461-480, 481-500,501-520, 521-540, 541-560, 561-580, 581-600, 601-620, 621-640, 641-660,661-680, 681-700, 701-720, 721-740, 741-760, 761-780, 781-800, 801-820,821-840, 841-860, 861-880, 881-900, 901-920, 921-940, 941-960, 961-980,981-1000, 1001-1020, 1021-1040, 1041-1060, 1061-1080, 1081-1100,1101-1120, 1121-1140, 1141-1160, 1161-1180, 1181-1200, 1201-1220,1221-1240, 1241-1260, 1261-1280, 1281-1300, 1301-1320, 1321-1340,1341-1360, 1361-1380, 1381-1400, 1401-1420, 1421-1440, or 1441 to theend of the coding region of SEQ ID NO:Y. Moreover, polypeptide fragmentsof the invention may be at least about 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, or 150amino acids in length. In this context “about” includes the particularlyrecited ranges or values, or ranges or values larger or smaller byseveral (5, 4, 3, 2, or 1) amino acids, at either extreme or at bothextremes. Polynucleotides encoding these polypeptide fragments are alsoencompassed by the invention.

Even if deletion of one or more amino acids from the N-terminus of aprotein results in modification of loss of one or more biologicalfunctions of the protein, other functional activities (e.g., biologicalactivities, ability to multimerize, ability to bind a ligand) may stillbe retained. For example, the ability of shortened muteins to induceand/or bind to antibodies which recognize the complete or mature formsof the polypeptides generally will be retained when less than themajority of the residues of the complete or mature polypeptide areremoved from the N-terminus. Whether a particular polypeptide lackingN-terminal residues of a complete polypeptide retains such immunologicactivities can readily be determined by routine methods described hereinand otherwise known in the art. It is not unlikely that a mutein with alarge number of deleted N-terminal amino acid residues may retain somebiological or immunogenic activities. In fact, peptides composed of asfew as six amino acid residues may often evoke an immune response.

Accordingly, polypeptide fragments include the secreted protein as wellas the mature form. Further preferred polypeptide fragments include thesecreted protein or the mature form having a continuous series ofdeleted residues from the amino or the carboxy terminus, or both. Forexample, any number of amino acids, ranging from 1-60, can be deletedfrom the amino terminus of either the secreted polypeptide or the matureform. Similarly, any number of amino acids, ranging from 1-30, can bedeleted from the carboxy terminus of the secreted protein or matureform. Furthermore, any combination of the above amino and carboxyterminus deletions are preferred. Similarly, polynucleotides encodingthese polypeptide fragments are also preferred.

The present invention further provides polypeptides having one or moreresidues deleted from the amino terminus of the amino acid sequence of apolypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, apolypeptide as defined in columns 14 and 15 of Table 1A, a polypeptideencoded by the polynucleotide sequence contained in SEQ ID NO:X or thecomplement thereof, a polypeptide encoded by the portion of SEQ ID NO:Xas defined in columns 8 and 9 of Table 2, a polypeptide encoded by theportion of SEQ ID NO:B as defined in column 6 of Table 1C, a polypeptideencoded by the cDNA contained in ATCC Deposit No: Z, and/or a maturepolypeptide encoded by the cDNA contained in ATCC Deposit No: Z). Inparticular, N-terminal deletions may be described by the general formulam-q, where q is a whole integer representing the total number of aminoacid residues in a polypeptide of the invention (e.g., the polypeptidedisclosed in SEQ ID NO:Y, the mature (secreted) portion of SEQ ID NO:Yas defined in columns 14 and 15 of Table 1A, or the polypeptide encodedby the portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2),and m is defined as any integer ranging from 2 to q-6. Polynucleotidesencoding these polypeptides are also encompassed by the invention.

The present invention further provides polypeptides having one or moreresidues from the carboxy terminus of the amino acid sequence of apolypeptide disclosed herein (e.g., a polypeptide of SEQ ID NO:Y, themature (secreted) portion of SEQ ID NO:Y as defined in columns 14 and 15of Table 1A, a polypeptide encoded by the polynucleotide sequencecontained in SEQ ID NO:X, a polypeptide encoded by the portion of SEQ IDNO:X as defined in columns 8 and 9 of Table 2, a polypeptide encoded bythe portion of SEQ ID NO:B as defined in column 6 of Table 1C, apolypeptide encoded by the cDNA contained in ATCC Deposit No: Z, and/ora mature polypeptide encoded by the cDNA contained in ATCC Deposit No:Z). In particular, C-terminal deletions may be described by the generalformula 1-n, where n is any whole integer ranging from 6 to q-1, andwhere n corresponds to the position of amino acid residue in apolypeptide of the invention. Polynucleotides encoding thesepolypeptides are also encompassed by the invention.

In addition, any of the above described N- or C-terminal deletions canbe combined to produce a N- and C-terminal deleted polypeptide. Theinvention also provides polypeptides having one or more amino acidsdeleted from both the amino and the carboxyl termini, which may bedescribed generally as having residues m-n of a polypeptide encoded bySEQ ID NO:X (e.g., including, but not limited to, the preferredpolypeptide disclosed as SEQ ID NO:Y, the mature (secreted) portion ofSEQ ID NO:Y as defined in columns 14 and 15 of Table 1A, and thepolypeptide encoded by the portion of SEQ ID NO:X as defined in columns8 and 9 of Table 2), the cDNA contained in ATCC Deposit No: Z, and/orthe complement thereof, where n and m are integers as described above.Polynucleotides encoding these polypeptides are also encompassed by theinvention.

Also as mentioned above, even if deletion of one or more amino acidsfrom the C-terminus of a protein results in modification of loss of oneor more biological functions of the protein, other functional activities(e.g., biological activities, ability to multimerize, ability to bind aligand) may still be retained. For example the ability of the shortenedmutein to induce and/or bind to antibodies which recognize the completeor mature forms of the polypeptide generally will be retained when lessthan the majority of the residues of the complete or mature polypeptideare removed from the C-terminus. Whether a particular polypeptidelacking C-terminal residues of a complete polypeptide retains suchimmunologic activities can readily be determined by routine methodsdescribed herein and otherwise known in the art. It is not unlikely thata mutein with a large number of deleted C-terminal amino acid residuesmay retain some biological or immunogenic activities. In fact, peptidescomposed of as few as six amino acid residues may often evoke an immuneresponse.

The present application is also directed to proteins containingpolypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identicalto a polypeptide sequence set forth herein. In preferred embodiments,the application is directed to proteins containing polypeptides at least80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to polypeptideshaving the amino acid sequence of the specific N- and C-terminaldeletions. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

Any polypeptide sequence encoded by, for example, the polynucleotidesequences set forth as SEQ ID NO:X or the complement thereof,(presented, for example, in Tables 1A and 2), the cDNA contained in ATCCDeposit No: Z, or the polynucleotide sequence as defined in column 6 ofTable 1C, may be analyzed to determine certain preferred regions of thepolypeptide. For example, the amino acid sequence of a polypeptideencoded by a polynucleotide sequence of SEQ ID NO:X (e.g., thepolypeptide of SEQ ID NO:Y and the polypeptide encoded by the portion ofSEQ ID NO:X as defined in columns 8 and 9 of Table 2) or the cDNAcontained in ATCC Deposit No: Z may be analyzed using the defaultparameters of the DNASTAR computer algorithm (DNASTAR, Inc., 1228 S.Park St., Madison, Wis. 53715 USA; http://www.dnastar.com/).

Polypeptide regions that may be routinely obtained using the DNASTARcomputer algorithm include, but are not limited to, Garnier-Robsonalpha-regions, beta-regions, turn-regions, and coil-regions; Chou-Fasmanalpha-regions, beta-regions, and turn-regions; Kyte-Doolittlehydrophilic regions and hydrophobic regions; Eisenberg alpha- andbeta-amphipathic regions; Karplus-Schulz flexible regions; Eminisurface-forming regions; and Jameson-Wolf regions of high antigenicindex. Among highly preferred polynucleotides of the invention in thisregard are those that encode polypeptides comprising regions thatcombine several structural features, such as several (e.g., 1, 2, 3 or4) of the features set out above.

Additionally, Kyte-Doolittle hydrophilic regions and hydrophobicregions, Emini surface-forming regions, and Jameson-Wolf regions of highantigenic index (i.e., containing four or more contiguous amino acidshaving an antigenic index of greater than or equal to 1.5, as identifiedusing the default parameters of the Jameson-Wolf program) can routinelybe used to determine polypeptide regions that exhibit a high degree ofpotential for antigenicity. Regions of high antigenicity are determinedfrom data by DNASTAR analysis by choosing values which represent regionsof the polypeptide which are likely to be exposed on the surface of thepolypeptide in an environment in which antigen recognition may occur inthe process of initiation of an immune response.

Preferred polypeptide fragments of the invention are fragmentscomprising, or alternatively, consisting of, an amino acid sequence thatdisplays a functional activity (e.g. biological activity) of thepolypeptide sequence of which the amino acid sequence is a fragment. Bya polypeptide displaying a “functional activity” is meant a polypeptidecapable of one or more known functional activities associated with afull-length protein, such as, for example, biological activity,antigenicity, immunogenicity, and/or multimerization, as describedherein.

Other preferred polypeptide fragments are biologically active fragments.Biologically active fragments are those exhibiting activity similar, butnot necessarily identical, to an activity of the polypeptide of thepresent invention. The biological activity of the fragments may includean improved desired activity, or a decreased undesirable activity.

In preferred embodiments, polypeptides of the invention comprise, oralternatively consist of, one, two, three, four, five or more of theantigenic fragments of the polypeptide of SEQ ID NO:Y, or portionsthereof. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

Epitopes and Antibodies

The present invention encompasses polypeptides comprising, oralternatively consisting of, an epitope of: the polypeptide sequenceshown in SEQ ID NO:Y; a polypeptide sequence encoded by SEQ ID NO:X orthe complementary strand thereto; the polypeptide sequence encoded bythe portion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2; thepolypeptide sequence encoded by the portion of SEQ ID NO:B as defined incolumn 6 of Table 1C or the complement thereto; the polypeptide sequenceencoded by the cDNA contained in ATCC Deposit No: Z; or the polypeptidesequence encoded by a polynucleotide that hybridizes to the sequence ofSEQ ID NO:X, the complement of the sequence of SEQ ID NO:X, thecomplement of a portion of SEQ ID NO:X as defined in columns 8 and 9 ofTable 2, or the cDNA sequence contained in ATCC Deposit No: Z understringent hybridization conditions or alternatively, under lowerstringency hybridization as defined supra. The present invention furtherencompasses polynucleotide sequences encoding an epitope of apolypeptide sequence of the invention (such as, for example, thesequence disclosed in SEQ ID NO:X, or a fragment thereof),polynucleotide sequences of the complementary strand of a polynucleotidesequence encoding an epitope of the invention, and polynucleotidesequences which hybridize to the complementary strand under stringenthybridization conditions or alternatively, under lower stringencyhybridization conditions defined supra.

The term “epitopes,” as used herein, refers to portions of a polypeptidehaving antigenic or immunogenic activity in an animal, preferably amammal, and most preferably in a human. In a preferred embodiment, thepresent invention encompasses a polypeptide comprising an epitope, aswell as the polynucleotide encoding this polypeptide. An “immunogenicepitope,” as used herein, is defined as a portion of a protein thatelicits an antibody response in an animal, as determined by any methodknown in the art, for example, by the methods for generating antibodiesdescribed infra. (See, for example, Geysen et al., Proc. Natl. Acad.Sci. USA 81:3998-4002 (1983)). The term “antigenic epitope,” as usedherein, is defined as a portion of a protein to which an antibody canimmunospecifically bind its antigen as determined by any method wellknown in the art, for example, by the immunoassays described herein.Immunospecific binding excludes non-specific binding but does notnecessarily exclude cross-reactivity with other antigens. Antigenicepitopes need not necessarily be immunogenic.

Fragments which function as epitopes may be produced by any conventionalmeans. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA82:5131-5135 (1985) further described in U.S. Pat. No. 4,631,211.)

In the present invention, antigenic epitopes preferably contain asequence of at least 4, at least 5, at least 6, at least 7, morepreferably at least 8, at least 9, at least 10, at least 11, at least12, at least 13, at least 14, at least 15, at least 20, at least 25, atleast 30, at least 40, at least 50, and, most preferably, between about15 to about 30 amino acids. Preferred polypeptides comprisingimmunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acidresidues in length. Additional non-exclusive preferred antigenicepitopes include the antigenic epitopes disclosed herein, as well asportions thereof. Antigenic epitopes are useful, for example, to raiseantibodies, including monoclonal antibodies, that specifically bind theepitope. Preferred antigenic epitopes include the antigenic epitopesdisclosed herein, as well as any combination of two, three, four, fiveor more of these antigenic epitopes. Antigenic epitopes can be used asthe target molecules in immunoassays. (See, for instance, Wilson et al.,Cell 37:767-778 (1984); Sutcliffe et al., Science 219:660-666 (1983)).

Non-limiting examples of epitopes of polypeptides that can be used togenerate antibodies of the invention include a polypeptide comprising,or alternatively consisting of, at least one, two, three, four, five,six or more of the portion(s) of SEQ ID NO:Y specified in column 6 ofTable 1B.1. These polypeptide fragments have been determined to bearantigenic epitopes of the proteins of the invention by the analysis ofthe Jameson-Wolf antigenic index which is included in the DNAStar suiteof computer programs. By “comprise” it is intended that a polypeptidecontains at least one, two, three, four, five, six or more of theportion(s) of SEQ ID NO:Y shown in column 6 of Table 1B.1, but it maycontain additional flanking residues on either the amino or carboxyltermini of the recited portion. Such additional flanking sequences arepreferably sequences naturally found adjacent to the portion; i.e.,contiguous sequence shown in SEQ ID NO:Y. The flanking sequence may,however, be sequences from a heterolgous polypeptide, such as fromanother protein described herein or from a heterologous polypeptide notdescribed herein. In particular embodiments, epitope portions of apolypeptide of the invention comprise one, two, three, or more of theportions of SEQ ID NO:Y shown in column 6 of Table 1B.1.

Similarly, immunogenic epitopes can be used, for example, to induceantibodies according to methods well known in the art. See, forinstance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al.,Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle et al., J. Gen. Virol.66:2347-2354 (1985). Preferred immunogenic epitopes include theimmunogenic epitopes disclosed herein, as well as any combination oftwo, three, four, five or more of these immunogenic epitopes. Thepolypeptides comprising one or more immunogenic epitopes may bepresented for eliciting an antibody response together with a carrierprotein, such as an albumin, to an animal system (such as rabbit ormouse), or, if the polypeptide is of sufficient length (at least about25 amino acids), the polypeptide may be presented without a carrier.However, immunogenic epitopes comprising as few as 8 to 10 amino acidshave been shown to be sufficient to raise antibodies capable of bindingto, at the very least, linear epitopes in a denatured polypeptide (e.g.,in Western blotting).

Epitope-bearing polypeptides of the present invention may be used toinduce antibodies according to methods well known in the art including,but not limited to, in vivo immunization, in vitro immunization, andphage display methods. See, e.g., Sutcliffe et al., supra; Wilson etal., supra, and Bittle et al., J. Gen. Virol., 66:2347-2354 (1985). Ifin vivo immunization is used, animals may be immunized with freepeptide; however, anti-peptide antibody titer may be boosted by couplingthe peptide to a macromolecular carrier, such as keyhole limpethemacyanin (KLH) or tetanus toxoid. For instance, peptides containingcysteine residues may be coupled to a carrier using a linker such asmaleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptidesmay be coupled to carriers using a more general linking agent such asglutaraldehyde. Animals such as rabbits, rats and mice are immunizedwith either free or carrier-coupled peptides, for instance, byintraperitoneal and/or intradermal injection of emulsions containingabout 100 μg of peptide or carrier protein and Freund's adjuvant or anyother adjuvant known for stimulating an immune response. Several boosterinjections may be needed, for instance, at intervals of about two weeks,to provide a useful titer of anti-peptide antibody which can bedetected, for example, by ELISA assay using free peptide adsorbed to asolid surface. The titer of anti-peptide antibodies in serum from animmunized animal may be increased by selection of anti-peptideantibodies, for instance, by adsorption to the peptide on a solidsupport and elution of the selected antibodies according to methods wellknown in the art.

As one of skill in the art will appreciate, and as discussed above, thepolypeptides of the present invention (e.g., those comprising animmunogenic or antigenic epitope) can be fused to heterologouspolypeptide sequences. For example, polypeptides of the presentinvention (including fragments or variants thereof), may be fused withthe constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portionsthereof (CH1, CH2, CH3, or any combination thereof and portions thereof,resulting in chimeric polypeptides. By way of another non-limitingexample, polypeptides and/or antibodies of the present invention(including fragments or variants thereof) may be fused with albumin(including but not limited to recombinant human serum albumin orfragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969,issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883,issued Jun. 16, 1998, herein incorporated by reference in theirentirety)). In a preferred embodiment, polypeptides and/or antibodies ofthe present invention (including fragments or variants thereof) arefused with the mature form of human serum albumin (i.e., amino acids1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0322 094) which is herein incorporated by reference in its entirety. Inanother preferred embodiment, polypeptides and/or antibodies of thepresent invention (including fragments or variants thereof) are fusedwith polypeptide fragments comprising, or alternatively consisting of,amino acid residues 1-z of human serum albumin, where z is an integerfrom 369 to 419, as described in U.S. Pat. No. 5,766,883 hereinincorporated by reference in its entirety. Polypeptides and/orantibodies of the present invention (including fragments or variantsthereof) may be fused to either the N- or C-terminal end of theheterologous protein (e.g., immunoglobulin Fc polypeptide or human serumalbumin polypeptide). Polynucleotides encoding fusion proteins of theinvention are also encompassed by the invention.

Such fusion proteins as those described above may facilitatepurification and may increase half-life in vivo. This has been shown forchimeric proteins consisting of the first two domains of the humanCD4-polypeptide and various domains of the constant regions of the heavyor light chains of mammalian immunoglobulins. See, e.g., EP 394,827;Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of anantigen across the epithelial barrier to the immune system has beendemonstrated for antigens (e.g., insulin) conjugated to an FcRn bindingpartner such as IgG or Fc fragments (see, e.g., PCT Publications WO96/22024 and WO 99/04813). IgG fusion proteins that have adisulfide-linked dimeric structure due to the IgG portion desulfidebonds have also been found to be more efficient in binding andneutralizing other molecules than monomeric polypeptides or fragmentsthereof alone. See, e.g., Fountoulakis et al., J. Biochem.,270:3958-3964 (1995). Nucleic acids encoding the above epitopes can alsobe recombined with a gene of interest as an epitope tag (e.g., thehemagglutinin (HA) tag or flag tag) to aid in detection and purificationof the expressed polypeptide. For example, a system described byJanknecht et al. allows for the ready purification of non-denaturedfusion proteins expressed in human cell lines (Janknecht et al., 1991,Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene ofinterest is subcloned into a vaccinia recombination plasmid such thatthe open reading frame of the gene is translationally fused to anamino-terminal tag consisting of six histidine residues. The tag servesas a matrix binding domain for the fusion protein. Extracts from cellsinfected with the recombinant vaccinia virus are loaded onto Ni2+nitriloacetic acid-agarose column and histidine-tagged proteins can beselectively eluted with imidazole-containing buffers.

Fusion Proteins

Any polypeptide of the present invention can be used to generate fusionproteins. For example, the polypeptide of the present invention, whenfused to a second protein, can be used as an antigenic tag. Antibodiesraised against the polypeptide of the present invention can be used toindirectly detect the second protein by binding to the polypeptide.Moreover, because secreted proteins target cellular locations based ontrafficking signals, polypeptides of the present invention which areshown to be secreted can be used as targeting molecules once fused toother proteins.

Examples of domains that can be fused to polypeptides of the presentinvention include not only heterologous signal sequences, but also otherheterologous functional regions. The fusion does not necessarily need tobe direct, but may occur through linker sequences.

In certain preferred embodiments, proteins of the invention are fusionproteins comprising an amino acid sequence that is an N and/orC-terminal deletion of a polypeptide of the invention. In preferredembodiments, the invention is directed to a fusion protein comprising anamino acid sequence that is at least 90%, 95%, 96%, 97%, 98% or 99%identical to a polypeptide sequence of the invention. Polynucleotidesencoding these proteins are also encompassed by the invention.

Moreover, fusion proteins may also be engineered to improvecharacteristics of the polypeptide of the present invention. Forinstance, a region of additional amino acids, particularly charged aminoacids, may be added to the N-terminus of the polypeptide to improvestability and persistence during purification from the host cell orsubsequent handling and storage. Also, peptide moieties may be added tothe polypeptide to facilitate purification. Such regions may be removedprior to final preparation of the polypeptide. The addition of peptidemoieties to facilitate handling of polypeptides are familiar and routinetechniques in the art.

As one of skill in the art will appreciate that, as discussed above,polypeptides of the present invention, and epitope-bearing fragmentsthereof, can be combined with heterologous polypeptide sequences. Forexample, the polypeptides of the present invention may be fused withheterologous polypeptide sequences, for example, the polypeptides of thepresent invention may be fused with the constant domain ofimmunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3,and any combination thereof, including both entire domains and portionsthereof), or albumin (including, but not limited to, native orrecombinant human albumin or fragments or variants thereof (see, e.g.,U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, andU.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated byreference in their entirety)), resulting in chimeric polypeptides. Forexample, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusionproteins comprising various portions of constant region ofimmunoglobulin molecules together with another human protein or partthereof. In many cases, the Fc part in a fusion protein is beneficial intherapy and diagnosis, and thus can result in, for example, improvedpharmacokinetic properties (EP-A 0232 262). Alternatively, deleting theFc part after the fusion protein has been expressed, detected, andpurified, would be desired. For example, the Fc portion may hindertherapy and diagnosis if the fusion protein is used as an antigen forimmunizations. In drug discovery, for example, human proteins, such ashIL-5, have been fused with Fc portions for the purpose ofhigh-throughput screening assays to identify antagonists of hIL-5. See,D. Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johansonet al., J. Biol. Chem. 270:9459-9471 (1995).

Moreover, the polypeptides of the present invention can be fused tomarker sequences, such as a polypeptide which facilitates purificationof the fused polypeptide. In preferred embodiments, the marker aminoacid sequence is a hexa-histidine peptide, such as the tag provided in apQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311),among others, many of which are commercially available. As described inGentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), forinstance, hexa-histidine provides for convenient purification of thefusion protein. Another peptide tag useful for purification, the “HA”tag, corresponds to an epitope derived from the influenza hemagglutininprotein (Wilson et al., Cell 37:767 (1984)).

Additional fusion proteins of the invention may be generated through thetechniques of gene-shuffling, motif-shuffling, exon-shuffling, and/orcodon-shuffling (collectively referred to as “DNA shuffling”). DNAshuffling may be employed to modulate the activities of polypeptides ofthe invention, such methods can be used to generate polypeptides withaltered activity, as well as agonists and antagonists of thepolypeptides. See, generally, U.S. Pat. Nos. 5,605,793; 5,811,238;5,830,721; 5,834,252; and 5,837,458, and Patten et al., Curr. OpinionBiotechnol. 8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82(1998); Hansson, et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzoand Blasco, Biotechniques 24(2):308-13 (1998) (each of these patents andpublications are hereby incorporated by reference in its entirety). Inone embodiment, alteration of polynucleotides corresponding to SEQ IDNO:X and the polypeptides encoded by these polynucleotides may beachieved by DNA shuffling. DNA shuffling involves the assembly of two ormore DNA segments by homologous or site-specific recombination togenerate variation in the polynucleotide sequence. In anotherembodiment, polynucleotides of the invention, or the encodedpolypeptides, may be altered by being subjected to random mutagenesis byerror-prone PCR, random nucleotide insertion or other methods prior torecombination. In another embodiment, one or more components, motifs,sections, parts, domains, fragments, etc., of a polynucleotide encodinga polypeptide of the invention may be recombined with one or morecomponents, motifs, sections, parts, domains, fragments, etc. of one ormore heterologous molecules.

Thus, any of these above fusions can be engineered using thepolynucleotides or the polypeptides of the present invention.

Recombinant and Synthetic Production of Polypeptides of the Invention

The present invention also relates to vectors containing thepolynucleotide of the present invention, host cells, and the productionof polypeptides by synthetic and recombinant techniques. The vector maybe, for example, a phage, plasmid, viral, or retroviral vector.Retroviral vectors may be replication competent or replicationdefective. In the latter case, viral propagation generally will occuronly in complementing host cells.

The polynucleotides of the invention may be joined to a vectorcontaining a selectable marker for propagation in a host. Generally, aplasmid vector is introduced in a precipitate, such as a calciumphosphate precipitate, or in a complex with a charged lipid. If thevector is a virus, it may be packaged in vitro using an appropriatepackaging cell line and then transduced into host cells.

The polynucleotide insert should be operatively linked to an appropriatepromoter, such as the phage lambda PL promoter, the E. coli lac, trp,phoA and tac promoters, the SV40 early and late promoters and promotersof retroviral LTRs, to name a few. Other suitable promoters will beknown to the skilled artisan. The expression constructs will furthercontain sites for transcription initiation, termination, and, in thetranscribed region, a ribosome binding site for translation. The codingportion of the transcripts expressed by the constructs will preferablyinclude a translation initiating codon at the beginning and atermination codon (UAA, UGA or UAG) appropriately positioned at the endof the polypeptide to be translated.

As indicated, the expression vectors will preferably include at leastone selectable marker. Such markers include dihydrofolate reductase,G418, glutamine synthase, or neomycin resistance for eukaryotic cellculture, and tetracycline, kanamycin or ampicillin resistance genes forculturing in E. coli and other bacteria. Representative examples ofappropriate hosts include, but are not limited to, bacterial cells, suchas E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells,such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris(ATCC Accession No. 201178)); insect cells such as Drosophila S2 andSpodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowesmelanoma cells; and plant cells. Appropriate culture mediums andconditions for the above-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 andpQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescriptvectors, pNH8A, pNH16a, pNH18A, pNH46A, available from StratageneCloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5available from Pharmacia Biotech, Inc. Among preferred eukaryoticvectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available fromStratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia.Preferred expression vectors for use in yeast systems include, but arenot limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ,pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, andPA0815 (all available from Invitrogen, Carlbad, Calif.). Other suitablevectors will be readily apparent to the skilled artisan.

Vectors which use glutamine synthase (GS) or DHFR as the selectablemarkers can be amplified in the presence of the drugs methioninesulphoximine or methotrexate, respectively. An advantage of glutaminesynthase based vectors are the availability of cell lines (e.g., themurine myeloma cell line, NS0) which are glutamine synthase negative.Glutamine synthase expression systems can also function in glutaminesynthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) byproviding additional inhibitor to prevent the functioning of theendogenous gene. A glutamine synthase expression system and componentsthereof are detailed in PCT publications: WO87/04462; WO86/05807;WO89/01036; WO89/10404; and WO91/06657, which are hereby incorporated intheir entireties by reference herein. Additionally, glutamine synthaseexpression vectors can be obtained from Lonza Biologics, Inc.(Portsmouth, N.H.). Expression and production of monoclonal antibodiesusing a GS expression system in murine myeloma cells is described inBebbington et al., Bio/technology 10:169(1992) and in Biblia andRobinson Biotechnol. Prog. 11:1 (1995) which are herein incorporated byreference.

The present invention also relates to host cells containing theabove-described vector constructs described herein, and additionallyencompasses host cells containing nucleotide sequences of the inventionthat are operably associated with one or more heterologous controlregions (e.g., promoter and/or enhancer) using techniques known of inthe art. The host cell can be a higher eukaryotic cell, such as amammalian cell (e.g., a human derived cell), or a lower eukaryotic cell,such as a yeast cell, or the host cell can be a prokaryotic cell, suchas a bacterial cell. A host strain may be chosen which modulates theexpression of the inserted gene sequences, or modifies and processes thegene product in the specific fashion desired. Expression from certainpromoters can be elevated in the presence of certain inducers; thusexpression of the genetically engineered polypeptide may be controlled.Furthermore, different host cells have characteristics and specificmechanisms for the translational and post-translational processing andmodification (e.g., phosphorylation, cleavage) of proteins. Appropriatecell lines can be chosen to ensure the desired modifications andprocessing of the foreign protein expressed.

Introduction of the nucleic acids and nucleic acid constructs of theinvention into the host cell can be effected by calcium phosphatetransfection, DEAE-dextran mediated transfection, cationiclipid-mediated transfection, electroporation, transduction, infection,or other methods. Such methods are described in many standard laboratorymanuals, such as Davis et al., Basic Methods In Molecular Biology(1986). It is specifically contemplated that the polypeptides of thepresent invention may in fact be expressed by a host cell lacking arecombinant vector.

In addition to encompassing host cells containing the vector constructsdiscussed herein, the invention also encompasses primary, secondary, andimmortalized host cells of vertebrate origin, particularly mammalianorigin, that have been engineered to delete or replace endogenousgenetic material (e.g., the coding sequence), and/or to include geneticmaterial (e.g., heterologous polynucleotide sequences) that is operablyassociated with polynucleotides of the invention, and which activates,alters, and/or amplifies endogenous polynucleotides. For example,techniques known in the art may be used to operably associateheterologous control regions (e.g., promoter and/or enhancer) andendogenous polynucleotide sequences via homologous recombination (see,e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; InternationalPublication Number WO 96/29411; International Publication Number WO94/12650; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989);and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of eachof which are incorporated by reference in their entireties).

Polypeptides of the invention can be recovered and purified fromrecombinant cell cultures by well-known methods including ammoniumsulfate or ethanol precipitation, acid extraction, anion or cationexchange chromatography, phosphocellulos chromatography, hydrophobicinteraction chromatography, affinity chromatography, hydroxylapatitechromatography and lectin chromatography. Most preferably, highperformance liquid charomatography (“HPLC”) is employed forpurification.

Polypeptides of the present invention can also be recovered from:products purified from natural sources, including bodily fluids, tissuesand cells, whether directly isolated or cultured; products of chemicalsynthetic procedures; and products produced by recombinant techniquesfrom a prokaryotic or eukaryotic host, including, for example,bacterial, yeast, higher plant, insect, and mammalian cells. Dependingupon the host employed in a recombinant production procedure, thepolypeptides of the present invention may be glycosylated or may benon-glycosylated. In addition, polypeptides of the invention may alsoinclude an initial modified methionine residue, in some cases as aresult of host-mediated processes. Thus, it is well known in the artthat the N-terminal methionine encoded by the translation initiationcodon generally is removed with high efficiency from any protein aftertranslation in all eukaryotic cells. While the N-terminal methionine onmost proteins also is efficiently removed in most prokaryotes, for someproteins, this prokaryotic removal process is inefficient, depending onthe nature of the amino acid to which the N-terminal methionine iscovalently linked.

In one embodiment, the yeast Pichia pastoris is used to expresspolypeptides of the invention in a eukaryotic system. Pichia pastoris isa methylotrophic yeast which can metabolize methanol as its sole carbonsource. A main step in the methanol metabolization pathway is theoxidation of methanol to formaldehyde using O₂. This reaction iscatalyzed by the enzyme alcohol oxidase. In order to metabolize methanolas its sole carbon source, Pichia pastoris must generate high levels ofalcohol oxidase due, in part, to the relatively low affinity of alcoholoxidase for O₂. Consequently, in a growth medium depending on methanolas a main carbon source, the promoter region of one of the two alcoholoxidase genes (AOX1) is highly active. In the presence of methanol,alcohol oxidase produced from the AOX1 gene comprises up toapproximately 30% of the total soluble protein in Pichia pastoris. SeeEllis, S. B., et al., Mol. Cell. Biol. 5:1111-21 (1985); Koutz, P. J, etal., Yeast 5:167-77 (1989); Tschopp, J. F., et al., Nucl. Acids Res.15:3859-76 (1987). Thus, a heterologous coding sequence, such as, forexample, a polynucleotide of the present invention, under thetranscriptional regulation of all or part of the AOX1 regulatorysequence is expressed at exceptionally high levels in Pichia yeast grownin the presence of methanol.

In one example, the plasmid vector pPIC9K is used to express DNAencoding a polypeptide of the invention, as set forth herein, in aPichea yeast system essentially as described in “Pichia Protocols:Methods in Molecular Biology,” D. R. Higgins and J. Cregg, eds. TheHumana Press, Totowa, N.J., 1998. This expression vector allowsexpression and secretion of a polypeptide of the invention by virtue ofthe strong AOX1 promoter linked to the Pichia pastoris alkalinephosphatase (PHO) secretory signal peptide (i.e., leader) locatedupstream of a multiple cloning site.

Many other yeast vectors could be used in place of pPIC9K, such as,pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9,pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, and PAO815, as one skilled in theart would readily appreciate, as long as the proposed expressionconstruct provides appropriately located signals for transcription,translation, secretion (if desired), and the like, including an in-frameAUG as required.

In another embodiment, high-level expression of a heterologous codingsequence, such as, for example, a polynucleotide of the presentinvention, may be achieved by cloning the heterologous polynucleotide ofthe invention into an expression vector such as, for example, pGAPZ orpGAPZalpha, and growing the yeast culture in the absence of methanol.

In addition to encompassing host cells containing the vector constructsdiscussed herein, the invention also encompasses primary, secondary, andimmortalized host cells of vertebrate origin, particularly mammalianorigin, that have been engineered to delete or replace endogenousgenetic material (e.g., coding sequence), and/or to include geneticmaterial (e.g., heterologous polynucleotide sequences) that is operablyassociated with polynucleotides of the invention, and which activates,alters, and/or amplifies endogenous polynucleotides. For example,techniques known in the art may be used to operably associateheterologous control regions (e.g., promoter and/or enhancer) andendogenous polynucleotide sequences via homologous recombination (see,e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; InternationalPublication No. WO 96/29411, published Sep. 26, 1996; InternationalPublication No. WO 94/12650, published Aug. 4, 1994; Koller et al.,Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al.,Nature 342:435-438 (1989), the disclosures of each of which areincorporated by reference in their entireties).

In addition, polypeptides of the invention can be chemically synthesizedusing techniques known in the art (e.g., see Creighton, 1983, Proteins:Structures and Molecular Principles, W.H. Freeman & Co., N.Y., andHunkapiller et al., Nature, 310:105-111 (1984)). For example, apolypeptide corresponding to a fragment of a polypeptide can besynthesized by use of a peptide synthesizer. Furthermore, if desired,nonclassical amino acids or chemical amino acid analogs can beintroduced as a substitution or addition into the polypeptide sequence.Non-classical amino acids include, but are not limited to, to theD-isomers of the common amino acids, 2,4-diaminobutyric acid, a-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu,e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline,sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine,t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine,fluoro-amino acids, designer amino acids such as b-methyl amino acids,Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs ingeneral. Furthermore, the amino acid can be D (dextrorotary) or L(levorotary).

The invention encompasses polypeptides of the present invention whichare differentially modified during or after translation, e.g., byglycosylation, acetylation, phosphorylation, amidation, derivatizationby known protecting/blocking groups, proteolytic cleavage, linkage to anantibody molecule or other cellular ligand, etc. Any of numerouschemical modifications may be carried out by known techniques, includingbut not limited, to specific chemical cleavage by cyanogen bromide,trypsin, chymotrypsin, papain, V8 protease, NaBH₄; acetylation,formylation, oxidation, reduction; metabolic synthesis in the presenceof tunicamycin; etc.

Additional post-translational modifications encompassed by the inventioninclude, for example, e.g., N-linked or O-linked carbohydrate chains,processing of N-terminal or C-terminal ends), attachment of chemicalmoieties to the amino acid backbone, chemical modifications of N-linkedor O-linked carbohydrate chains, and addition or deletion of anN-terminal methionine residue as a result of procaryotic host cellexpression. The polypeptides may also be modified with a detectablelabel, such as an enzymatic, fluorescent, isotopic or affinity label toallow for detection and isolation of the protein.

Examples of suitable enzymes include horseradish peroxidase, alkalinephosphatase, beta-galactosidase, or acetylcholinesterase; examples ofsuitable prosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin;and examples of suitable radioactive material include iodine (¹²¹I,¹²³I, ¹²⁵I, ¹³¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium(¹¹¹In, ¹¹²In, ^(113m)In, ^(115m)In), technetium (⁹⁹Tc, ^(99m)Tc),thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum(⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm,¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, and ⁹⁷Ru.

In specific embodiments, a polypeptide of the present invention orfragment or variant thereof is attached to macrocyclic chelators thatassociate with radiometal ions, including but not limited to, ¹⁷⁷Lu,⁹⁰Y, ¹⁶⁶Ho, and ¹⁵³Sm, to polypeptides. In a preferred embodiment, theradiometal ion associated with the macrocyclic chelators is ¹¹¹In. Inanother preferred embodiment, the radiometal ion associated with themacrocyclic chelator is ⁹⁰Y. In specific embodiments, the macrocyclicchelator is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid(DOTA). In other specific embodiments, DOTA is attached to an antibodyof the invention or fragment thereof via a linker molecule. Examples oflinker molecules useful for conjugating DOTA to a polypeptide arecommonly known in the art—see, for example, DeNardo et al., Clin CancerRes. 4(10):2483-90 (1998); Peterson et al., Bioconjug. Chem. 10(4):553-7(1999); and Zimmerman et al, Nucl. Med. Biol. 26(8):943-50 (1999); whichare hereby incorporated by reference in their entirety.

As mentioned, the proteins of the invention may be modified by eithernatural processes, such as posttranslational processing, or by chemicalmodification techniques which are well known in the art. It will beappreciated that the same type of modification may be present in thesame or varying degrees at several sites in a given polypeptide.Polypeptides of the invention may be branched, for example, as a resultof ubiquitination, and they may be cyclic, with or without branching.Cyclic, branched, and branched cyclic polypeptides may result fromposttranslation natural processes or may be made by synthetic methods.Modifications include acetylation, acylation, ADP-ribosylation,amidation, covalent attachment of flavin, covalent attachment of a hememoiety, covalent attachment of a nucleotide or nucleotide derivative,covalent attachment of a lipid or lipid derivative, covalent attachmentof phosphotidylinositol, cross-linking, cyclization, disulfide bondformation, demethylation, formation of covalent cross-links, formationof cysteine, formation of pyroglutamate, formylation,gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation,iodination, methylation, myristoylation, oxidation, pegylation,proteolytic processing, phosphorylation, prenylation, racemization,selenoylation, sulfation, transfer-RNA mediated addition of amino acidsto proteins such as arginylation, and ubiquitination. (See, forinstance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.Creighton, W.H. Freeman and Company, New York (1993); POSTTRANSLATIONALCOVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press,New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646(1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

Also provided by the invention are chemically modified derivatives ofthe polypeptides of the invention which may provide additionaladvantages such as increased solubility, stability and circulating timeof the polypeptide, or decreased immunogenicity (see U.S. Pat. No.4,179,337). The chemical moieties for derivitization may be selectedfrom water soluble polymers such as polyethylene glycol, ethyleneglycol/propylene glycol copolymers, carboxymethylcellulose, dextran,polyvinyl alcohol and the like. The polypeptides may be modified atrandom positions within the molecule, or at predetermined positionswithin the molecule and may include one, two, three or more attachedchemical moieties.

The polymer may be of any molecular weight, and may be branched orunbranched. For polyethylene glycol, the preferred molecular weight isbetween about 1 kDa and about 100 kDa (the term “about” indicating thatin preparations of polyethylene glycol, some molecules will weigh more,some less, than the stated molecular weight) for ease in handling andmanufacturing. Other sizes may be used, depending on the desiredtherapeutic profile (e.g., the duration of sustained release desired,the effects, if any on biological activity, the ease in handling, thedegree or lack of antigenicity and other known effects of thepolyethylene glycol to a therapeutic protein or analog). For example,the polyethylene glycol may have an average molecular weight of about200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500,6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000,11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500,16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000,25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000,70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.

As noted above, the polyethylene glycol may have a branched structure.Branched polyethylene glycols are described, for example, in U.S. Pat.No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol. 56:59-72(1996); Vorobjev et al, Nucleosides Nucleotides 18:2745-2750 (1999); andCaliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosures ofeach of which are incorporated herein by reference.

The polyethylene glycol molecules (or other chemical moieties) should beattached to the protein with consideration of effects on functional orantigenic domains of the protein. There are a number of attachmentmethods available to those skilled in the art, such as, for example, themethod disclosed in EP 0 401 384 (coupling PEG to G-CSF), hereinincorporated by reference; see also Malik et al., Exp. Hematol.20:1028-1035 (1992), reporting pegylation of GM-CSF using tresylchloride. For example, polyethylene glycol may be covalently boundthrough amino acid residues via a reactive group, such as a free aminoor carboxyl group. Reactive groups are those to which an activatedpolyethylene glycol molecule may be bound. The amino acid residueshaving a free amino group may include lysine residues and the N-terminalamino acid residues; those having a free carboxyl group may includeaspartic acid residues glutamic acid residues and the C-terminal aminoacid residue. Sulfhydryl groups may also be used as a reactive group forattaching the polyethylene glycol molecules. Preferred for therapeuticpurposes is attachment at an amino group, such as attachment at theN-terminus or lysine group.

As suggested above, polyethylene glycol may be attached to proteins vialinkage to any of a number of amino acid residues. For example,polyethylene glycol can be linked to proteins via covalent bonds tolysine, histidine, aspartic acid, glutamic acid, or cysteine residues.One or more reaction chemistries may be employed to attach polyethyleneglycol to specific amino acid residues (e.g., lysine, histidine,aspartic acid, glutamic acid, or cysteine) of the protein or to morethan one type of amino acid residue (e.g., lysine, histidine, asparticacid, glutamic acid, cysteine and combinations thereof) of the protein.

One may specifically desire proteins chemically modified at theN-terminus. Using polyethylene glycol as an illustration of the presentcomposition, one may select from a variety of polyethylene glycolmolecules (by molecular weight, branching, etc.), the proportion ofpolyethylene glycol molecules to protein (polypeptide) molecules in thereaction mix, the type of pegylation reaction to be performed, and themethod of obtaining the selected N-terminally pegylated protein. Themethod of obtaining the N-terminally pegylated preparation (i.e.,separating this moiety from other monopegylated moieties if necessary)may be by purification of the N-terminally pegylated material from apopulation of pegylated protein molecules. Selective proteins chemicallymodified at the N-terminus modification may be accomplished by reductivealkylation which exploits differential reactivity of different types ofprimary amino groups (lysine versus the N-terminal) available forderivatization in a particular protein. Under the appropriate reactionconditions, substantially selective derivatization of the protein at theN-terminus with a carbonyl group containing polymer is achieved.

As indicated above, pegylation of the proteins of the invention may beaccomplished by any number of means. For example, polyethylene glycolmay be attached to the protein either directly or by an interveninglinker. Linkerless systems for attaching polyethylene glycol to proteinsare described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys.9:249-304 (1992); Francis et al., Intern. J. of Hematol. 68:1-18 (1998);U.S. Pat. No. 4,002,531; U.S. Pat. No. 5,349,052; WO 95/06058; and WO98/32466, the disclosures of each of which are incorporated herein byreference.

One system for attaching polyethylene glycol directly to amino acidresidues of proteins without an intervening linker employs tresylatedMPEG, which is produced by the modification of monmethoxy polyethyleneglycol (MPEG) using tresylchloride (ClSO₂CH₂CF₃). Upon reaction ofprotein with tresylated MPEG, polyethylene glycol is directly attachedto amine groups of the protein. Thus, the invention includesprotein-polyethylene glycol conjugates produced by reacting proteins ofthe invention with a polyethylene glycol molecule having a2,2,2-trifluoreothane sulphonyl group.

Polyethylene glycol can also be attached to proteins using a number ofdifferent intervening linkers. For example, U.S. Pat. No. 5,612,460, theentire disclosure of which is incorporated herein by reference,discloses urethane linkers for connecting polyethylene glycol toproteins. Protein-polyethylene glycol conjugates wherein thepolyethylene glycol is attached to the protein by a linker can also beproduced by reaction of proteins with compounds such asMPEG-succinimidylsuccinate, MPEG activated with1,1′-carbonyldiimidazole, MPEG-2,4,5-trichloropenylcarbonate,MPEG-p-nitrophenolcarbonate, and various MPEG-succinate derivatives. Anumber of additional polyethylene glycol derivatives and reactionchemistries for attaching polyethylene glycol to proteins are describedin International Publication No. WO 98/32466, the entire disclosure ofwhich is incorporated herein by reference. Pegylated protein productsproduced using the reaction chemistries set out herein are includedwithin the scope of the invention.

The number of polyethylene glycol moieties attached to each protein ofthe invention (i.e., the degree of substitution) may also vary. Forexample, the pegylated proteins of the invention may be linked, onaverage, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or morepolyethylene glycol molecules. Similarly, the average degree ofsubstitution within ranges such as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9,8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or18-20 polyethylene glycol moieties per protein molecule. Methods fordetermining the degree of substitution are discussed, for example, inDelgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992).

The polypeptides of the invention can be recovered and purified fromchemical synthesis and recombinant cell cultures by standard methodswhich include, but are not limited to, ammonium sulfate or ethanolprecipitation, acid extraction, anion or cation exchange chromatography,phosphocellulose chromatography, hydrophobic interaction chromatography,affinity chromatography, hydroxylapatite chromatography and lectinchromatography. Most preferably, high performance liquid chromatography(“HPLC”) is employed for purification. Well known techniques forrefolding protein may be employed to regenerate active conformation whenthe polypeptide is denatured during isolation and/or purification.

The polypeptides of the invention may be in monomers or multimers (i.e.,dimers, trimers, tetramers and higher multimers). Accordingly, thepresent invention relates to monomers and multimers of the polypeptidesof the invention, their preparation, and compositions (preferably,Therapeutics) containing them. In specific embodiments, the polypeptidesof the invention are monomers, dimers, trimers or tetramers. Inadditional embodiments, the multimers of the invention are at leastdimers, at least trimers, or at least tetramers.

Multimers encompassed by the invention may be homomers or heteromers. Asused herein, the term homomer refers to a multimer containing onlypolypeptides corresponding to a protein of the invention (e.g., theamino acid sequence of SEQ ID NO:Y, an amino acid sequence encoded bySEQ ID NO:X or the complement of SEQ ID NO:X, the amino acid sequenceencoded by the portion of SEQ ID NO:X as defined in columns 8 and 9 ofTable 2, and/or an amino acid sequence encoded by cDNA contained in ATCCDeposit No: Z (including fragments, variants, splice variants, andfusion proteins, corresponding to these as described herein)). Thesehomomers may contain polypeptides having identical or different aminoacid sequences. In a specific embodiment, a homomer of the invention isa multimer containing only polypeptides having an identical amino acidsequence. In another specific embodiment, a homomer of the invention isa multimer containing polypeptides having different amino acidsequences. In specific embodiments, the multimer of the invention is ahomodimer (e.g., containing two polypeptides having identical ordifferent amino acid sequences) or a homotrimer (e.g., containing threepolypeptides having identical and/or different amino acid sequences). Inadditional embodiments, the homomeric multimer of the invention is atleast a homodimer, at least a homotrimer, or at least a homotetramer.

As used herein, the term heteromer refers to a multimer containing oneor more heterologous polypeptides (i.e., polypeptides of differentproteins) in addition to the polypeptides of the invention. In aspecific embodiment, the multimer of the invention is a heterodimer, aheterotrimer, or a heterotetramer. In additional embodiments, theheteromeric multimer of the invention is at least a heterodimer, atleast a heterotrimer, or at least a heterotetramer.

Multimers of the invention may be the result of hydrophobic,hydrophilic, ionic and/or covalent associations and/or may be indirectlylinked by, for example, liposome formation. Thus, in one embodiment,multimers of the invention, such as, for example, homodimers orhomotrimers, are formed when polypeptides of the invention contact oneanother in solution. In another embodiment, heteromultimers of theinvention, such as, for example, heterotrimers or heterotetramers, areformed when polypeptides of the invention contact antibodies to thepolypeptides of the invention (including antibodies to the heterologouspolypeptide sequence in a fusion protein of the invention) in solution.In other embodiments, multimers of the invention are formed by covalentassociations with and/or between the polypeptides of the invention. Suchcovalent associations may involve one or more amino acid residuescontained in the polypeptide sequence (e.g., that recited in SEQ IDNO:Y, encoded by the portion of SEQ ID NO:X as defined in columns 8 and9 of Table 2, and/or encoded by the cDNA contained in ATCC Deposit No:Z). In one instance, the covalent associations are cross-linking betweencysteine residues located within the polypeptide sequences whichinteract in the native (i.e., naturally occurring) polypeptide. Inanother instance, the covalent associations are the consequence ofchemical or recombinant manipulation. Alternatively, such covalentassociations may involve one or more amino acid residues contained inthe heterologous polypeptide sequence in a fusion protein. In oneexample, covalent associations are between the heterologous sequencecontained in a fusion protein of the invention (see, e.g., U.S. Pat. No.5,478,925). In a specific example, the covalent associations are betweenthe heterologous sequence contained in a Fc fusion protein of theinvention (as described herein). In another specific example, covalentassociations of fusion proteins of the invention are betweenheterologous polypeptide sequence from another protein that is capableof forming covalently associated multimers, such as for example,osteoprotegerin (see, e.g., International Publication NO: WO 98/49305,the contents of which are herein incorporated by reference in itsentirety). In another embodiment, two or more polypeptides of theinvention are joined through peptide linkers. Examples include thosepeptide linkers described in U.S. Pat. No. 5,073,627 (herebyincorporated by reference). Proteins comprising multiple polypeptides ofthe invention separated by peptide linkers may be produced usingconventional recombinant DNA technology.

Another method for preparing multimer polypeptides of the inventioninvolves use of polypeptides of the invention fused to a leucine zipperor isoleucine zipper polypeptide sequence. Leucine zipper and isoleucinezipper domains are polypeptides that promote multimerization of theproteins in which they are found. Leucine zippers were originallyidentified in several DNA-binding proteins (Landschulz et al., Science240:1759, (1988)), and have since been found in a variety of differentproteins. Among the known leucine zippers are naturally occurringpeptides and derivatives thereof that dimerize or trimerize. Examples ofleucine zipper domains suitable for producing soluble multimericproteins of the invention are those described in PCT application WO94/10308, hereby incorporated by reference. Recombinant fusion proteinscomprising a polypeptide of the invention fused to a polypeptidesequence that dimerizes or trimerizes in solution are expressed insuitable host cells, and the resulting soluble multimeric fusion proteinis recovered from the culture supernatant using techniques known in theart.

Trimeric polypeptides of the invention may offer the advantage ofenhanced biological activity. Preferred leucine zipper moieties andisoleucine moieties are those that preferentially form trimers. Oneexample is a leucine zipper derived from lung surfactant protein D(SPD), as described in Hoppe et al. (FEBS Letters 344:191, (1994)) andin U.S. patent application Ser. No. 08/446,922, hereby incorporated byreference. Other peptides derived from naturally occurring trimericproteins may be employed in preparing trimeric polypeptides of theinvention.

In another example, proteins of the invention are associated byinteractions between Flag® polypeptide sequence contained in fusionproteins of the invention containing Flag® polypeptide sequence. In afurther embodiment, proteins of the invention are associated byinteractions between heterologous polypeptide sequence contained inFlag® fusion proteins of the invention and anti-Flag® antibody.

The multimers of the invention may be generated using chemicaltechniques known in the art. For example, polypeptides desired to becontained in the multimers of the invention may be chemicallycross-linked using linker molecules and linker molecule lengthoptimization techniques known in the art (see, e.g., U.S. Pat. No.5,478,925, which is herein incorporated by reference in its entirety).Additionally, multimers of the invention may be generated usingtechniques known in the art to form one or more inter-moleculecross-links between the cysteine residues located within the sequence ofthe polypeptides desired to be contained in the multimer (see, e.g.,U.S. Pat. No. 5,478,925, which is herein incorporated by reference inits entirety). Further, polypeptides of the invention may be routinelymodified by the addition of cysteine or biotin to the C-terminus orN-terminus of the polypeptide and techniques known in the art may beapplied to generate multimers containing one or more of these modifiedpolypeptides (see, e.g., U.S. Pat. No. 5,478,925, which is hereinincorporated by reference in its entirety). Additionally, techniquesknown in the art may be applied to generate liposomes containing thepolypeptide components desired to be contained in the multimer of theinvention (see, e.g., U.S. Pat. No. 5,478,925, which is hereinincorporated by reference in its entirety).

Alternatively, multimers of the invention may be generated using geneticengineering techniques known in the art. In one embodiment, polypeptidescontained in multimers of the invention are produced recombinantly usingfusion protein technology described herein or otherwise known in the art(see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated byreference in its entirety). In a specific embodiment, polynucleotidescoding for a homodimer of the invention are generated by ligating apolynucleotide sequence encoding a polypeptide of the invention to asequence encoding a linker polypeptide and then further to a syntheticpolynucleotide encoding the translated product of the polypeptide in thereverse orientation from the original C-terminus to the N-terminus(lacking the leader sequence) (see, e.g., U.S. Pat. No. 5,478,925, whichis herein incorporated by reference in its entirety). In anotherembodiment, recombinant techniques described herein or otherwise knownin the art are applied to generate recombinant polypeptides of theinvention which contain a transmembrane domain (or hydrophobic or signalpeptide) and which can be incorporated by membrane reconstitutiontechniques into liposomes (see, e.g., U.S. Pat. No. 5,478,925, which isherein incorporated by reference in its entirety).

Antibodies

Further polypeptides of the invention relate to antibodies and T-cellantigen receptors (TCR) which immunospecifically bind a polypeptide,polypeptide fragment, or variant of the invention (e.g., a polypeptideor fragment or variant of the amino acid sequence of SEQ ID NO:Y or apolypeptide encoded by the cDNA contained in ATCC Deposit No: Z, and/oran epitope, of the present invention) as determined by immunoassays wellknown in the art for assaying specific antibody-antigen binding.Antibodies of the invention include, but are not limited to, polyclonal,monoclonal, multispecific, human, humanized or chimeric antibodies,single chain antibodies, Fab fragments, F(ab′) fragments, fragmentsproduced by a Fab expression library, anti-idiotypic (anti-Id)antibodies (including, e.g., anti-Id antibodies to antibodies of theinvention), intracellularly-made antibodies (i.e., intrabodies), andepitope-binding fragments of any of the above. The term “antibody,” asused herein, refers to immunoglobulin molecules and immunologicallyactive portions of immunoglobulin molecules, i.e., molecules thatcontain an antigen binding site that immunospecifically binds anantigen. The immunoglobulin molecules of the invention can be of anytype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2,IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. Inpreferred embodiments, the immunoglobulin molecules of the invention areIgG1. In other preferred embodiments, the immunoglobulin molecules ofthe invention are IgG4.

Most preferably the antibodies are human antigen-binding antibodyfragments of the present invention and include, but are not limited to,Fab, Fab′ and F(ab′)2, Fd, single-chain Fvs (scFv), single-chainantibodies, disulfide-linked Fvs (sdFv) and fragments comprising eithera VL or VH domain. Antigen-binding antibody fragments, includingsingle-chain antibodies, may comprise the variable region(s) alone or incombination with the entirety or a portion of the following: hingeregion, CH1, CH2, and CH3 domains. Also included in the invention areantigen-binding fragments also comprising any combination of variableregion(s) with a hinge region, CH1, CH2, and CH3 domains. The antibodiesof the invention may be from any animal origin including birds andmammals. Preferably, the antibodies are human, murine (e.g., mouse andrat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken.As used herein, “human” antibodies include antibodies having the aminoacid sequence of a human immunoglobulin and include antibodies isolatedfrom human immunoglobulin libraries or from animals transgenic for oneor more human immunoglobulin and that do not express endogenousimmunoglobulins, as described infra and, for example in, U.S. Pat. No.5,939,598 by Kucherlapati et al. The antibodies of the present inventionmay be monospecific, bispecific, trispecific or of greatermultispecificity. Multispecific antibodies may be specific for differentepitopes of a polypeptide of the present invention or may be specificfor both a polypeptide of the present invention as well as for aheterologous epitope, such as a heterologous polypeptide or solidsupport material. See, e.g., PCT publications WO 93/17715; WO 92/08802;WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991);U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819;Kostelny et al., J. Immunol. 148:1547-1553 (1992).

Antibodies of the present invention may be described or specified interms of the epitope(s) or portion(s) of a polypeptide of the presentinvention which they recognize or specifically bind. The epitope(s) orpolypeptide portion(s) may be specified as described herein, e.g., byN-terminal and C-terminal positions, or by size in contiguous amino acidresidues, or listed in the Tables and Figures. Preferred epitopes of theinvention include the predicted epitopes shown in column 6 of Table1B.1, as well as polynucleotides that encode these epitopes. Antibodieswhich specifically bind any epitope or polypeptide of the presentinvention may also be excluded. Therefore, the present inventionincludes antibodies that specifically bind polypeptides of the presentinvention, and allows for the exclusion of the same.

Antibodies of the present invention may also be described or specifiedin terms of their cross-reactivity. Antibodies that do not bind anyother analog, ortholog, or homolog of a polypeptide of the presentinvention are included. Antibodies that bind polypeptides with at least95%, at least 90%, at least 85%, at least 80%, at least 75%, at least70%, at least 65%, at least 60%, at least 55%, and at least 50% identity(as calculated using methods known in the art and described herein) to apolypeptide of the present invention are also included in the presentinvention. In specific embodiments, antibodies of the present inventioncross-react with murine, rat and/or rabbit homologs of human proteinsand the corresponding epitopes thereof. Antibodies that do not bindpolypeptides with less than 95%, less than 90%, less than 85%, less than80%, less than 75%, less than 70%, less than 65%, less than 60%, lessthan 55%, and less than 50% identity (as calculated using methods knownin the art and described herein) to a polypeptide of the presentinvention are also included in the present invention. In a specificembodiment, the above-described cross-reactivity is with respect to anysingle specific antigenic or immunogenic polypeptide, or combination(s)of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenicpolypeptides disclosed herein. Further included in the present inventionare antibodies which bind polypeptides encoded by polynucleotides whichhybridize to a polynucleotide of the present invention under stringenthybridization conditions (as described herein). Antibodies of thepresent invention may also be described or specified in terms of theirbinding affinity to a polypeptide of the invention. Preferred bindingaffinities include those with a dissociation constant or Kd less than5×10⁻² M, 10⁻² M, 5×10⁻³ M, 10⁻³ M, 5×10⁻⁴ M, 10⁻⁴ M, 5×10⁻⁵ M, 10⁻⁵ M,5×10⁻⁶ M, 10⁻⁶M, 5×10⁻⁷ M, 10⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10⁻⁹ M, 10⁻⁹ M,5×10⁻¹⁰ M, 10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³ M,10⁻¹³ M, 5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, or 10⁻¹⁵ M.

The invention also provides antibodies that competitively inhibitbinding of an antibody to an epitope of the invention as determined byany method known in the art for determining competitive binding, forexample, the immunoassays described herein. In preferred embodiments,the antibody competitively inhibits binding to the epitope by at least95%, at least 90%, at least 85%, at least 80%, at least 75%, at least70%, at least 60%, or at least 50%.

Antibodies of the present invention may act as agonists or antagonistsof the polypeptides of the present invention. For example, the presentinvention includes antibodies which disrupt the receptor/ligandinteractions with the polypeptides of the invention either partially orfully. Preferably, antibodies of the present invention bind an antigenicepitope disclosed herein, or a portion thereof. The invention featuresboth receptor-specific antibodies and ligand-specific antibodies. Theinvention also features receptor-specific antibodies which do notprevent ligand binding but prevent receptor activation. Receptoractivation (i.e., signaling) may be determined by techniques describedherein or otherwise known in the art. For example, receptor activationcan be determined by detecting the phosphorylation (e.g., tyrosine orserine/threonine) of the receptor or its substrate byimmunoprecipitation followed by western blot analysis (for example, asdescribed supra). In specific embodiments, antibodies are provided thatinhibit ligand activity or receptor activity by at least 95%, at least90%, at least 85%, at least 80%, at least 75%, at least 70%, at least60%, or at least 50% of the activity in absence of the antibody.

The invention also features receptor-specific antibodies which bothprevent ligand binding and receptor activation as well as antibodiesthat recognize the receptor-ligand complex, and, preferably, do notspecifically recognize the unbound receptor or the unbound ligand.Likewise, included in the invention are neutralizing antibodies whichbind the ligand and prevent binding of the ligand to the receptor, aswell as antibodies which bind the ligand, thereby preventing receptoractivation, but do not prevent the ligand from binding the receptor.Further included in the invention are antibodies which activate thereceptor. These antibodies may act as receptor agonists, i.e.,potentiate or activate either all or a subset of the biologicalactivities of the ligand-mediated receptor activation, for example, byinducing dimerization of the receptor. The antibodies may be specifiedas agonists, antagonists or inverse agonists for biological activitiescomprising the specific biological activities of the peptides of theinvention disclosed herein. The above antibody agonists can be madeusing methods known in the art. See, e.g., PCT publication WO 96/40281;U.S. Pat. No. 5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chenet al., Cancer Res. 58(16):3668-3678 (1998); Harrop et al., J. Immunol.161(4):1786-1794 (1998); Zhu et al., Cancer Res. 58(15):3209-3214(1998); Yoon et al., J. Immunol. 160(7):3170-3179 (1998); Prat et al.,J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J. Immunol.Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241(1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997);Taryman et al., Neuron 14(4):755-762 (1995); Muller et al., Structure6(9):1153-1167 (1998); Bartunek et al., Cytokine 8(1):14-20 (1996)(which are all incorporated by reference herein in their entireties).

Antibodies of the present invention may be used, for example, to purify,detect, and target the polypeptides of the present invention, includingboth in vitro and in vivo diagnostic and therapeutic methods. Forexample, the antibodies have utility in immunoassays for qualitativelyand quantitatively measuring levels of the polypeptides of the presentinvention in biological samples. See, e.g., Harlow et al., Antibodies: ALaboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988);incorporated by reference herein in its entirety.

As discussed in more detail below, the antibodies of the presentinvention may be used either alone or in combination with othercompositions. The antibodies may further be recombinantly fused to aheterologous polypeptide at the N- or C-terminus or chemicallyconjugated (including covalent and non-covalent conjugations) topolypeptides or other compositions. For example, antibodies of thepresent invention may be recombinantly fused or conjugated to moleculesuseful as labels in detection assays and effector molecules such asheterologous polypeptides, drugs, radionuclides, or toxins. See, e.g.,PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No.5,314,995; and EP 396,387; the disclosures of which are incorporatedherein by reference in their entireties.

The antibodies of the invention include derivatives that are modified,i.e, by the covalent attachment of any type of molecule to the antibodysuch that covalent attachment does not prevent the antibody fromgenerating an anti-idiotypic response. For example, but not by way oflimitation, the antibody derivatives include antibodies that have beenmodified, e.g., by glycosylation, acetylation, pegylation,phosphylation, amidation, derivatization by known protecting/blockinggroups, proteolytic cleavage, linkage to a cellular ligand or otherprotein, etc. Any of numerous chemical modifications may be carried outby known techniques, including, but not limited to specific chemicalcleavage, acetylation, formylation, metabolic synthesis of tunicamycin,etc. Additionally, the derivative may contain one or more non-classicalamino acids.

The antibodies of the present invention may be generated by any suitablemethod known in the art. Polyclonal antibodies to an antigen-of-interestcan be produced by various procedures well known in the art. Forexample, a polypeptide of the invention can be administered to varioushost animals including, but not limited to, rabbits, mice, rats, etc. toinduce the production of sera containing polyclonal antibodies specificfor the antigen. Various adjuvants may be used to increase theimmunological response, depending on the host species, and include butare not limited to, Freund's (complete and incomplete), mineral gelssuch as aluminum hydroxide, surface active substances such aslysolecithin, pluronic polyols, polyanions, peptides, oil emulsions,keyhole limpet hemocyanins, dinitrophenol, and potentially useful humanadjuvants such as BCG (bacille Calmette-Guerin) and corynebacteriumparvum. Such adjuvants are also well known in the art.

Monoclonal antibodies can be prepared using a wide variety of techniquesknown in the art including the use of hybridoma, recombinant, and phagedisplay technologies, or a combination thereof. For example, monoclonalantibodies can be produced using hybridoma techniques including thoseknown in the art and taught, for example, in Harlow et al., Antibodies:A Laboratory Manual, (Cold Spring Harbor Laboratory Press; 2nd ed.1988); Hammerling, et al., in: Monoclonal Antibodies and T-CellHybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporatedby reference in their entireties). The term “monoclonal antibody” asused herein is not limited to antibodies produced through hybridomatechnology. The term “monoclonal antibody” refers to an antibody that isderived from a single clone, including any eukaryotic, prokaryotic, orphage clone, and not the method by which it is produced.

Methods for producing and screening for specific antibodies usinghybridoma technology are routine and well known in the art and arediscussed in detail in the Examples. In a non-limiting example, mice canbe immunized with a polypeptide of the invention or a cell expressingsuch peptide. Once an immune response is detected, e.g., antibodiesspecific for the antigen are detected in the mouse serum, the mousespleen is harvested and splenocytes isolated. The splenocytes are thenfused by well known techniques to any suitable myeloma cells, forexample cells from cell line SP20 available from the ATCC. Hybridomasare selected and cloned by limited dilution. The hybridoma clones arethen assayed by methods known in the art for cells that secreteantibodies capable of binding a polypeptide of the invention. Ascitesfluid, which generally contains high levels of antibodies, can begenerated by immunizing mice with positive hybridoma clones.

Accordingly, the present invention provides methods of generatingmonoclonal antibodies as well as antibodies produced by the methodcomprising culturing a hybridoma cell secreting an antibody of theinvention wherein, preferably, the hybridoma is generated by fusingsplenocytes isolated from a mouse immunized with an antigen of theinvention with myeloma cells and then screening the hybridomas resultingfrom the fusion for hybridoma clones that secrete an antibody able tobind a polypeptide of the invention.

Another well known method for producing both polyclonal and monoclonalhuman B cell lines is transformation using Epstein Barr Virus (EBV).Protocols for generating EBV-transformed B cell lines are commonly knownin the art, such as, for example, the protocol outlined in Chapter 7.22of Current Protocols in Immunology, Coligan et al., Eds., 1994, JohnWiley & Sons, NY, which is hereby incorporated in its entirety byreference. The source of B cells for transformation is commonly humanperipheral blood, but B cells for transformation may also be derivedfrom other sources including, but not limited to, lymph nodes, tonsil,spleen, tumor tissue, and infected tissues. Tissues are generally madeinto single cell suspensions prior to EBV transformation. Additionally,steps may be taken to either physically remove or inactivate T cells(e.g., by treatment with cyclosporin A) in B cell-containing samples,because T cells from individuals seropositive for anti-EBV antibodiescan suppress B cell immortalization by EBV.

In general, the sample containing human B cells is innoculated with EBV,and cultured for 3-4 weeks. A typical source of EBV is the culturesupernatant of the B95-8 cell line (ATCC #VR-1492). Physical signs ofEBV transformation can generally be seen towards the end of the 3-4 weekculture period. By phase-contrast microscopy, transformed cells mayappear large, clear, hairy and tend to aggregate in tight clusters ofcells. Initially, EBV lines are generally polyclonal. However, overprolonged periods of cell cultures, EBV lines may become monoclonal orpolyclonal as a result of the selective outgrowth of particular B cellclones. Alternatively, polyclonal EBV transformed lines may be subcloned(e.g., by limiting dilution culture) or fused with a suitable fusionpartner and plated at limiting dilution to obtain monoclonal B celllines. Suitable fusion partners for EBV transformed cell lines includemouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma celllines (human×mouse; e.g, SPAM-8, SBC-H20, and CB-F7), and human celllines (e.g., GM 1500, SKO-007, RPMI 8226, and KR-4). Thus, the presentinvention also provides a method of generating polyclonal or monoclonalhuman antibodies against polypeptides of the invention or fragmentsthereof, comprising EBV-transformation of human B cells.

Antibody fragments which recognize specific epitopes may be generated byknown techniques. For example, Fab and F(ab′)2 fragments of theinvention may be produced by proteolytic cleavage of immunoglobulinmolecules, using enzymes such as papain (to produce Fab fragments) orpepsin (to produce F(ab′)2 fragments). F(ab′)2 fragments contain thevariable region, the light chain constant region and the CH1 domain ofthe heavy chain.

For example, the antibodies of the present invention can also begenerated using various phage display methods known in the art. In phagedisplay methods, functional antibody domains are displayed on thesurface of phage particles which carry the polynucleotide sequencesencoding them. In a particular embodiment, such phage can be utilized todisplay antigen binding domains expressed from a repertoire orcombinatorial antibody library (e.g., human or murine). Phage expressingan antigen binding domain that binds the antigen of interest can beselected or identified with antigen, e.g., using labeled antigen orantigen bound or captured to a solid surface or bead. Phage used inthese methods are typically filamentous phage including fd and M13binding domains expressed from phage with Fab, Fv or disulfidestabilized Fv antibody domains recombinantly fused to either the phagegene III or gene VIII protein. Examples of phage display methods thatcan be used to make the antibodies of the present invention includethose disclosed in Brinkman et al., J. Immunol. Methods 182:41-50(1995); Ames et al., J. Immunol. Methods 184:177-186 (1995);Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994); Persic et al.,Gene 187 9-18 (1997); Burton et al., Advances in Immunology 57:191-280(1994); PCT application No. PCT/GB91/01134; PCT publications WO90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409;5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698;5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108;each of which is incorporated herein by reference in its entirety.

As described in the above references, after phage selection, theantibody coding regions from the phage can be isolated and used togenerate whole antibodies, including human antibodies, or any otherdesired antigen binding fragment, and expressed in any desired host,including mammalian cells, insect cells, plant cells, yeast, andbacteria, e.g., as described in detail below. For example, techniques torecombinantly produce Fab, Fab′ and F(ab′)2 fragments can also beemployed using methods known in the art such as those disclosed in PCTpublication WO 92/22324; Mullinax et al., BioTechniques 12(6):864-869(1992); and Sawai et al., AJRI 34:26-34 (1995); and Better et al.,Science 240:1041-1043 (1988) (said references incorporated by referencein their entireties).

Examples of techniques which can be used to produce single-chain Fvs andantibodies include those described in U.S. Pat. Nos. 4,946,778 and5,258,498; Huston et al., Methods in Enzymology 203:46-88 (1991); Shu etal., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040(1988). For some uses, including in vivo use of antibodies in humans andin vitro detection assays, it may be preferable to use chimeric,humanized, or human antibodies. A chimeric antibody is a molecule inwhich different portions of the antibody are derived from differentanimal species, such as antibodies having a variable region derived froma murine monoclonal antibody and a human immunoglobulin constant region.Methods for producing chimeric antibodies are known in the art. Seee.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214(1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; U.S.Pat. Nos. 5,807,715; 4,816,567; and 4,816,397, which are incorporatedherein by reference in their entirety. Humanized antibodies are antibodymolecules from non-human species antibody that binds the desired antigenhaving one or more complementarity determining regions (CDRs) from thenon-human species and a framework regions from a human immunoglobulinmolecule. Often, framework residues in the human framework regions willbe substituted with the corresponding residue from the CDR donorantibody to alter, preferably improve, antigen binding. These frameworksubstitutions are identified by methods well known in the art, e.g., bymodeling of the interactions of the CDR and framework residues toidentify framework residues important for antigen binding and sequencecomparison to identify unusual framework residues at particularpositions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmannet al., Nature 332:323 (1988), which are incorporated herein byreference in their entireties.) Antibodies can be humanized using avariety of techniques known in the art including, for example,CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos.5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498(1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994);Roguska. et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Pat.No. 5,565,332).

Completely human antibodies are particularly desirable for therapeutictreatment of human patients. Human antibodies can be made by a varietyof methods known in the art including phage display methods describedabove using antibody libraries derived from human immunoglobulinsequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCTpublications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO96/34096, WO 96/33735, and WO 91/10741; each of which is incorporatedherein by reference in its entirety.

Human antibodies can also be produced using transgenic mice which areincapable of expressing functional endogenous immunoglobulins, but whichcan express human immunoglobulin genes. For example, the human heavy andlight chain immunoglobulin gene complexes may be introduced randomly orby homologous recombination into mouse embryonic stem cells.Alternatively, the human variable region, constant region, and diversityregion may be introduced into mouse embryonic stem cells in addition tothe human heavy and light chain genes. The mouse heavy and light chainimmunoglobulin genes may be rendered non-functional separately orsimultaneously with the introduction of human immunoglobulin loci byhomologous recombination. In particular, homozygous deletion of the JHregion prevents endogenous antibody production. The modified embryonicstem cells are expanded and microinjected into blastocysts to producechimeric mice. The chimeric mice are then bred to produce homozygousoffspring which express human antibodies. The transgenic mice areimmunized in the normal fashion with a selected antigen, e.g., all or aportion of a polypeptide of the invention. Monoclonal antibodiesdirected against the antigen can be obtained from the immunized,transgenic mice using conventional hybridoma technology. The humanimmunoglobulin transgenes harbored by the transgenic mice rearrangeduring B cell differentiation, and subsequently undergo class switchingand somatic mutation. Thus, using such a technique, it is possible toproduce therapeutically useful IgG, IgA, IgM and IgE antibodies. For anoverview of this technology for producing human antibodies, see Lonbergand Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detaileddiscussion of this technology for producing human antibodies and humanmonoclonal antibodies and protocols for producing such antibodies, see,e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923;5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318;5,885,793; 5,916,771; 5,939,598; 6,075,181; and 6,114,598, which areincorporated by reference herein in their entirety. In addition,companies such as Abgenix, Inc. (Freemont, Calif.) and Genpharm (SanJose, Calif.) can be engaged to provide human antibodies directedagainst a selected antigen using technology similar to that describedabove.

Completely human antibodies which recognize a selected epitope can begenerated using a technique referred to as “guided selection.” In thisapproach a selected non-human monoclonal antibody, e.g., a mouseantibody, is used to guide the selection of a completely human antibodyrecognizing the same epitope. (Jespers et al., Bio/technology 12:899-903(1988)).

Further, antibodies to the polypeptides of the invention can, in turn,be utilized to generate anti-idiotype antibodies that “mimic”polypeptides of the invention using techniques well known to thoseskilled in the art. (See, e.g., Greenspan & Bona, FASEB J. 7(5):437-444;(1989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example,antibodies which bind to and competitively inhibit polypeptidemultimerization and/or binding of a polypeptide of the invention to aligand can be used to generate anti-idiotypes that “mimic” thepolypeptide multimerization and/or binding domain and, as a consequence,bind to and neutralize polypeptide and/or its ligand. Such neutralizinganti-idiotypes or Fab fragments of such anti-idiotypes can be used intherapeutic regimens to neutralize polypeptide ligand(s)/receptor(s).For example, such anti-idiotypic antibodies can be used to bind apolypeptide of the invention and/or to bind its ligand(s)/receptor(s),and thereby block its biological activity. Alternatively, antibodieswhich bind to and enhance polypeptide multimerization and/or binding,and/or receptor/ligand multimerization, binding and/or signaling can beused to generate anti-idiotypes that function as agonists of apolypeptide of the invention and/or its ligand/receptor. Such agonisticanti-idiotypes or Fab fragments of such anti-idiotypes can be used intherapeutic regimens as agonists of the polypeptides of the invention orits ligand(s)/receptor(s). For example, such anti-idiotypic antibodiescan be used to bind a polypeptide of the invention and/or to bind itsligand(s)/receptor(s), and thereby promote or enhance its biologicalactivity.

Intrabodies of the invention can be produced using methods known in theart, such as those disclosed and reviewed in Chen et al., Hum. GeneTher. 5:595-601 (1994); Marasco, W. A., Gene Ther. 4:11-15 (1997);Rondon and Marasco, Annu. Rev. Microbiol. 51:257-283 (1997); Proba etal., J. Mol. Biol. 275:245-253 (1998); Cohen et al., Oncogene17:2445-2456 (1998); Ohage and Steipe, J. Mol. Biol. 291:1119-1128(1999); Ohage et al., J. Mol. Biol. 291:1129-1134 (1999); Wirtz andSteipe, Protein Sci. 8:2245-2250 (1999); Zhu et al., J. Immunol. Methods231:207-222 (1999); and references cited therein.

Polynucleotides Encoding Antibodies

The invention further provides polynucleotides comprising a nucleotidesequence encoding an antibody of the invention and fragments thereof.The invention also encompasses polynucleotides that hybridize understringent or alternatively, under lower stringency hybridizationconditions, e.g., as defined supra, to polynucleotides that encode anantibody, preferably, that specifically binds to a polypeptide of theinvention, preferably, an antibody that binds to a polypeptide havingthe amino acid sequence of SEQ ID NO:Y, to a polypeptide encoded by aportion of SEQ ID NO:X as defined in columns 8 and 9 of Table 2, and/orto a polypeptide encoded by the cDNA contained in ATCC Deposit No: Z.

The polynucleotides may be obtained, and the nucleotide sequence of thepolynucleotides determined, by any method known in the art. For example,if the nucleotide sequence of the antibody is known, a polynucleotideencoding the antibody may be assembled from chemically synthesizedoligonucleotides (e.g., as described in Kutmeier et al., BioTechniques17:242 (1994)), which, briefly, involves the synthesis of overlappingoligonucleotides containing portions of the sequence encoding theantibody, annealing and ligating of those oligonucleotides, and thenamplification of the ligated oligonucleotides by PCR.

Alternatively, a polynucleotide encoding an antibody may be generatedfrom nucleic acid from a suitable source. If a clone containing anucleic acid encoding a particular antibody is not available, but thesequence of the antibody molecule is known, a nucleic acid encoding theimmunoglobulin may be chemically synthesized or obtained from a suitablesource (e.g., an antibody cDNA library, or a cDNA library generatedfrom, or nucleic acid, preferably poly A+ RNA, isolated from, any tissueor cells expressing the antibody, such as hybridoma cells selected toexpress an antibody of the invention) by PCR amplification usingsynthetic primers hybridizable to the 3′ and 5′ ends of the sequence orby cloning using an oligonucleotide probe specific for the particulargene sequence to identify, e.g., a cDNA clone from a cDNA library thatencodes the antibody. Amplified nucleic acids generated by PCR may thenbe cloned into replicable cloning vectors using any method well known inthe art.

Once the nucleotide sequence and corresponding amino acid sequence ofthe antibody is determined, the nucleotide sequence of the antibody maybe manipulated using methods well known in the art for the manipulationof nucleotide sequences, e.g., recombinant DNA techniques, site directedmutagenesis, PCR, etc. (see, for example, the techniques described inSambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed.,Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. and Ausubel etal., eds., 1998, Current Protocols in Molecular Biology, John Wiley &Sons, NY, which are both incorporated by reference herein in theirentireties), to generate antibodies having a different amino acidsequence, for example to create amino acid substitutions, deletions,and/or insertions.

In a specific embodiment, the amino acid sequence of the heavy and/orlight chain variable domains may be inspected to identify the sequencesof the complementarity determining regions (CDRs) by methods that arewell know in the art, e.g., by comparison to known amino acid sequencesof other heavy and light chain variable regions to determine the regionsof sequence hypervariability. Using routine recombinant DNA techniques,one or more of the CDRs may be inserted within framework regions, e.g.,into human framework regions to humanize a non-human antibody, asdescribed supra. The framework regions may be naturally occurring orconsensus framework regions, and preferably human framework regions(see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for alisting of human framework regions). Preferably, the polynucleotidegenerated by the combination of the framework regions and CDRs encodesan antibody that specifically binds a polypeptide of the invention.Preferably, as discussed supra, one or more amino acid substitutions maybe made within the framework regions, and, preferably, the amino acidsubstitutions improve binding of the antibody to its antigen.Additionally, such methods may be used to make amino acid substitutionsor deletions of one or more variable region cysteine residuesparticipating in an intrachain disulfide bond to generate antibodymolecules lacking one or more intrachain disulfide bonds. Otheralterations to the polynucleotide are encompassed by the presentinvention and within the skill of the art.

In addition, techniques developed for the production of “chimericantibodies” (Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984);Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature314:452-454 (1985)) by splicing genes from a mouse antibody molecule ofappropriate antigen specificity together with genes from a humanantibody molecule of appropriate biological activity can be used. Asdescribed supra, a chimeric antibody is a molecule in which differentportions are derived from different animal species, such as those havinga variable region derived from a murine mAb and a human immunoglobulinconstant region, e.g., humanized antibodies.

Alternatively, techniques described for the production of single chainantibodies (U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988);Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Wardet al., Nature 334:544-54 (1989)) can be adapted to produce single chainantibodies. Single chain antibodies are formed by linking the heavy andlight chain fragments of the Fv region via an amino acid bridge,resulting in a single chain polypeptide. Techniques for the assembly offunctional Fv fragments in E. coli may also be used (Skerra et al.,Science 242:1038-1041 (1988)).

Methods of Producing Antibodies

The antibodies of the invention can be produced by any method known inthe art for the synthesis of antibodies, in particular, by chemicalsynthesis or preferably, by recombinant expression techniques. Methodsof producing antibodies include, but are not limited to, hybridomatechnology, EBV transformation, and other methods discussed herein aswell as through the use recombinant DNA technology, as discussed below.

Recombinant expression of an antibody of the invention, or fragment,derivative or analog thereof, (e.g., a heavy or light chain of anantibody of the invention or a single chain antibody of the invention),requires construction of an expression vector containing apolynucleotide that encodes the antibody. Once a polynucleotide encodingan antibody molecule or a heavy or light chain of an antibody, orportion thereof (preferably containing the heavy or light chain variabledomain), of the invention has been obtained, the vector for theproduction of the antibody molecule may be produced by recombinant DNAtechnology using techniques well known in the art. Thus, methods forpreparing a protein by expressing a polynucleotide containing anantibody encoding nucleotide sequence are described herein. Methodswhich are well known to those skilled in the art can be used toconstruct expression vectors containing antibody coding sequences andappropriate transcriptional and translational control signals. Thesemethods include, for example, in vitro recombinant DNA techniques,synthetic techniques, and in vivo genetic recombination. The invention,thus, provides replicable vectors comprising a nucleotide sequenceencoding an antibody molecule of the invention, or a heavy or lightchain thereof, or a heavy or light chain variable domain, operablylinked to a promoter. Such vectors may include the nucleotide sequenceencoding the constant region of the antibody molecule (see, e.g., PCTPublication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No.5,122,464) and the variable domain of the antibody may be cloned intosuch a vector for expression of the entire heavy or light chain.

The expression vector is transferred to a host cell by conventionaltechniques and the transfected cells are then cultured by conventionaltechniques to produce an antibody of the invention. Thus, the inventionincludes host cells containing a polynucleotide encoding an antibody ofthe invention, or a heavy or light chain thereof, or a single chainantibody of the invention, operably linked to a heterologous promoter.In preferred embodiments for the expression of double-chainedantibodies, vectors encoding both the heavy and light chains may beco-expressed in the host cell for expression of the entireimmunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to expressthe antibody molecules of the invention. Such host-expression systemsrepresent vehicles by which the coding sequences of interest may beproduced and subsequently purified, but also represent cells which may,when transformed or transfected with the appropriate nucleotide codingsequences, express an antibody molecule of the invention in situ. Theseinclude but are not limited to microorganisms such as bacteria (e.g., E.coli, B. subtilis) transformed with recombinant bacteriophage DNA,plasmid DNA or cosmid DNA expression vectors containing antibody codingsequences; yeast (e.g., Saccharomyces, Pichia) transformed withrecombinant yeast expression vectors containing antibody codingsequences; insect cell systems infected with recombinant virusexpression vectors (e.g., baculovirus) containing antibody codingsequences; plant cell systems infected with recombinant virus expressionvectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus,TMV) or transformed with recombinant plasmid expression vectors (e.g.,Ti plasmid) containing antibody coding sequences; or mammalian cellsystems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinantexpression constructs containing promoters derived from the genome ofmammalian cells (e.g., metallothionein promoter) or from mammalianviruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5Kpromoter). Preferably, bacterial cells such as Escherichia coli, andmore preferably, eukaryotic cells, especially for the expression ofwhole recombinant antibody molecule, are used for the expression of arecombinant antibody molecule. For example, mammalian cells such asChinese hamster ovary cells (CHO), in conjunction with a vector such asthe major intermediate early gene promoter element from humancytomegalovirus is an effective expression system for antibodies(Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2(1990)).

In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the antibodymolecule being expressed. For example, when a large quantity of such aprotein is to be produced, for the generation of pharmaceuticalcompositions of an antibody molecule, vectors which direct theexpression of high levels of fusion protein products that are readilypurified may be desirable. Such vectors include, but are not limited, tothe E. coli expression vector pUR278 (Ruther et al., EMBO J. 2:1791(1983)), in which the antibody coding sequence may be ligatedindividually into the vector in frame with the lac Z coding region sothat a fusion protein is produced; pIN vectors (Inouye & Inouye, NucleicAcids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem.24:5503-5509 (1989)); and the like. pGEX vectors may also be used toexpress foreign polypeptides as fusion proteins with glutathioneS-transferase (GST). In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption and binding tomatrix glutathione-agarose beads followed by elution in the presence offree glutathione. The pGEX vectors are designed to include thrombin orfactor Xa protease cleavage sites so that the cloned target gene productcan be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus(AcNPV) is used as a vector to express foreign genes. The virus grows inSpodoptera frugiperda cells. The antibody coding sequence may be clonedindividually into non-essential regions (for example the polyhedringene) of the virus and placed under control of an AcNPV promoter (forexample the polyhedrin promoter).

In mammalian host cells, a number of viral-based expression systems maybe utilized. In cases where an adenovirus is used as an expressionvector, the antibody coding sequence of interest may be ligated to anadenovirus transcription/translation control complex, e.g., the latepromoter and tripartite leader sequence. This chimeric gene may then beinserted in the adenovirus genome by in vitro or in vivo recombination.Insertion in a non-essential region of the viral genome (e.g., region E1or E3) will result in a recombinant virus that is viable and capable ofexpressing the antibody molecule in infected hosts. (e.g., see Logan &Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)). Specificinitiation signals may also be required for efficient translation ofinserted antibody coding sequences. These signals include the ATGinitiation codon and adjacent sequences. Furthermore, the initiationcodon must be in phase with the reading frame of the desired codingsequence to ensure translation of the entire insert. These exogenoustranslational control signals and initiation codons can be of a varietyof origins, both natural and synthetic. The efficiency of expression maybe enhanced by the inclusion of appropriate transcription enhancerelements, transcription terminators, etc. (see Bittner et al., Methodsin Enzymol. 153:51-544 (1987)).

In addition, a host cell strain may be chosen which modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK,293, 3T3, WI38, and in particular, breast cancer cell lines such as, forexample, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary glandcell line such as, for example, CRL7030 and Hs578Bst.

For long-term, high-yield production of recombinant proteins, stableexpression is preferred. For example, cell lines which stably expressthe antibody molecule may be engineered. Rather than using expressionvectors which contain viral origins of replication, host cells can betransformed with DNA controlled by appropriate expression controlelements (e.g., promoter, enhancer, sequences, transcriptionterminators, polyadenylation sites, etc.), and a selectable marker.Following the introduction of the foreign DNA, engineered cells may beallowed to grow for 1-2 days in an enriched media, and then are switchedto a selective media. The selectable marker in the recombinant plasmidconfers resistance to the selection and allows cells to stably integratethe plasmid into their chromosomes and grow to form foci which in turncan be cloned and expanded into cell lines. This method mayadvantageously be used to engineer cell lines which express the antibodymolecule. Such engineered cell lines may be particularly useful inscreening and evaluation of compounds that interact directly orindirectly with the antibody molecule.

A number of selection systems may be used, including but not limited tothe herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223(1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska &Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adeninephosphoribosyltransferase (Lowy et al., Cell 22:817 (1980)) genes can beemployed in tk-, hgprt- or aprt-cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigleret al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl.Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072(1981)); neo, which confers resistance to the aminoglycoside G-418Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991);Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan,Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem.62:191-217 (1993); May, 1993, TIB TECH 11(5):155-215 (1993)); and hygro,which confers resistance to hygromycin (Santerre et al., Gene 30:147(1984)). Methods commonly known in the art of recombinant DNA technologymay be routinely applied to select the desired recombinant clone, andsuch methods are described, for example, in Ausubel et al. (eds.),Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993);Kriegler, Gene Transfer and Expression, A Laboratory Manual, StocktonPress, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds),Current Protocols in Human Genetics, John Wiley & Sons, NY (1994);Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which areincorporated by reference herein in their entireties.

The expression levels of an antibody molecule can be increased by vectoramplification (for a review, see Bebbington and Hentschel, The use ofvectors based on gene amplification for the expression of cloned genesin mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York,1987)). When a marker in the vector system expressing antibody isamplifiable, increase in the level of inhibitor present in culture ofhost cell will increase the number of copies of the marker gene. Sincethe amplified region is associated with the antibody gene, production ofthe antibody will also increase (Crouse et al., Mol. Cell. Biol. 3:257(1983)).

Vectors which use glutamine synthase (GS) or DHFR as the selectablemarkers can be amplified in the presence of the drugs methioninesulphoximine or methotrexate, respectively. An advantage of glutaminesynthase based vectors are the availability of cell lines (e.g., themurine myeloma cell line, NS0) which are glutamine synthase negative.Glutamine synthase expression systems can also function in glutaminesynthase expressing cells (e.g. Chinese Hamster Ovary (CHO) cells) byproviding additional inhibitor to prevent the functioning of theendogenous gene. A glutamine synthase expression system and componentsthereof are detailed in PCT publications: WO87/04462; WO86/05807;WO89/01036; WO89/10404; and WO91/06657 which are incorporated in theirentireties by reference herein. Additionally, glutamine synthaseexpression vectors that may be used according to the present inventionare commercially available from suplliers, including, for example LonzaBiologics, Inc. (Portsmouth, N.H.). Expression and production ofmonoclonal antibodies using a GS expression system in murine myelomacells is described in Bebbington et al., Bio/technology 10:169(1992) andin Biblia and Robinson Biotechnol. Prog. 11:1 (1995) which areincorporated in their entirities by reference herein.

The host cell may be co-transfected with two expression vectors of theinvention, the first vector encoding a heavy chain derived polypeptideand the second vector encoding a light chain derived polypeptide. Thetwo vectors may contain identical selectable markers which enable equalexpression of heavy and light chain polypeptides. Alternatively, asingle vector may be used which encodes, and is capable of expressing,both heavy and light chain polypeptides. In such situations, the lightchain should be placed before the heavy chain to avoid an excess oftoxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc.Natl. Acad. Sci. USA 77:2197 (1980)). The coding sequences for the heavyand light chains may comprise cDNA or genomic DNA.

Once an antibody molecule of the invention has been produced by ananimal, chemically synthesized, or recombinantly expressed, it may bepurified by any method known in the art for purification of animmunoglobulin molecule, for example, by chromatography (e.g., ionexchange, affinity, particularly by affinity for the specific antigenafter Protein A, and sizing column chromatography), centrifugation,differential solubility, or by any other standard technique for thepurification of proteins. In addition, the antibodies of the presentinvention or fragments thereof can be fused to heterologous polypeptidesequences described herein or otherwise known in the art, to facilitatepurification.

The present invention encompasses antibodies recombinantly fused orchemically conjugated (including both covalently and non-covalentlyconjugations) to a polypeptide (or portion thereof, preferably at least10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of thepolypeptide) of the present invention to generate fusion proteins. Thefusion does not necessarily need to be direct, but may occur throughlinker sequences. The antibodies may be specific for antigens other thanpolypeptides (or portion thereof, preferably at least 10, 20, 30, 40,50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the presentinvention. For example, antibodies may be used to target thepolypeptides of the present invention to particular cell types, eitherin vitro or in vivo, by fusing or conjugating the polypeptides of thepresent invention to antibodies specific for particular cell surfacereceptors. Antibodies fused or conjugated to the polypeptides of thepresent invention may also be used in in vitro immunoassays andpurification methods using methods known in the art. See e.g., Harbor etal., supra, and PCT publication WO 93/21232; EP 439,095; Naramura etal., Immunol. Lett. 39:91-99 (1994); U.S. Pat. No. 5,474,981; Gillies etal., PNAS 89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452(1991), which are incorporated by reference in their entireties.

The present invention further includes compositions comprising thepolypeptides of the present invention fused or conjugated to antibodydomains other than the variable regions. For example, the polypeptidesof the present invention may be fused or conjugated to an antibody Fcregion, or portion thereof. The antibody portion fused to a polypeptideof the present invention may comprise the constant region, hinge region,CH1 domain, CH2 domain, and CH3 domain or any combination of wholedomains or portions thereof. The polypeptides may also be fused orconjugated to the above antibody portions to form multimers. Forexample, Fc portions fused to the polypeptides of the present inventioncan form dimers through disulfide bonding between the Fc portions.Higher multimeric forms can be made by fusing the polypeptides toportions of IgA and IgM. Methods for fusing or conjugating thepolypeptides of the present invention to antibody portions are known inthe art. See, e.g., U.S. Pat. Nos. 5,336,603; 5,622,929; 5,359,046;5,349,053; 5,447,851; 5,112,946; EP 307,434; EP 367,166; PCTpublications WO 96/04388; WO 91/06570; Ashkenazi et al., Proc. Natl.Acad. Sci. USA 88:10535-10539 (1991); Zheng et al., J. Immunol.154:5590-5600 (1995); and Vil et al., Proc. Natl. Acad. Sci. USA89:11337-11341 (1992) (said references incorporated by reference intheir entireties).

As discussed, supra, the polypeptides corresponding to a polypeptide,polypeptide fragment, or a variant of SEQ ID NO:Y may be fused orconjugated to the above antibody portions to increase the in vivo halflife of the polypeptides or for use in immunoassays using methods knownin the art. Further, the polypeptides corresponding to SEQ ID NO:Y maybe fused or conjugated to the above antibody portions to facilitatepurification. One reported example describes chimeric proteinsconsisting of the first two domains of the human CD4-polypeptide andvarious domains of the constant regions of the heavy or light chains ofmammalian immunoglobulins. See EP 394,827; and Traunecker et al., Nature331:84-86 (1988). The polypeptides of the present invention fused orconjugated to an antibody having disulfide-linked dimeric structures(due to the IgG) may also be more efficient in binding and neutralizingother molecules, than the monomeric secreted protein or protein fragmentalone. See, for example, Fountoulakis et al., J. Biochem. 270:3958-3964(1995). In many cases, the Fc part in a fusion protein is beneficial intherapy and diagnosis, and thus can result in, for example, improvedpharmacokinetic properties. See, for example, EP A 232,262.Alternatively, deleting the Fc part after the fusion protein has beenexpressed, detected, and purified, would be desired. For example, the Fcportion may hinder therapy and diagnosis if the fusion protein is usedas an antigen for immunizations. In drug discovery, for example, humanproteins, such as hIL-5, have been fused with Fc portions for thepurpose of high-throughput screening assays to identify antagonists ofhIL-5. (See, Bennett et al., J. Molecular Recognition 8:52-58 (1995);Johanson et al., J. Biol. Chem. 270:9459-9471 (1995)).

Moreover, the antibodies or fragments thereof of the present inventioncan be fused to marker sequences, such as a peptide to facilitatepurification. In preferred embodiments, the marker amino acid sequenceis a hexa-histidine peptide, such as the tag provided in a pQE vector(QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), amongothers, many of which are commercially available. As described in Gentzet al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance,hexa-histidine provides for convenient purification of the fusionprotein. Other peptide tags useful for purification include, but are notlimited to, the “HA” tag, which corresponds to an epitope derived fromthe influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984))and the “flag” tag.

The present invention further encompasses antibodies or fragmentsthereof conjugated to a diagnostic or therapeutic agent. The antibodiescan be used diagnostically to, for example, monitor the development orprogression of a tumor as part of a clinical testing procedure to, e.g.,determine the efficacy of a given treatment regimen. Detection can befacilitated by coupling the antibody to a detectable substance. Examplesof detectable substances include various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,radioactive materials, positron emitting metals using various positronemission tomographies, and nonradioactive paramagnetic metal ions. Thedetectable substance may be coupled or conjugated either directly to theantibody (or fragment thereof) or indirectly, through an intermediate(such as, for example, a linker known in the art) using techniques knownin the art. See, for example, U.S. Pat. No. 4,741,900 for metal ionswhich can be conjugated to antibodies for use as diagnostics accordingto the present invention. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin; and examples of suitable radioactive materialinclude 125I, 131I, 111In or 99Tc.

Further, an antibody or fragment thereof may be conjugated to atherapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidalagent, a therapeutic agent or a radioactive metal ion, e.g.,alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxicagent includes any agent that is detrimental to cells. Examples includepaclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine,mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin,doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone,mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids,procaine, tetracaine, lidocaine, propranolol, and puromycin and analogsor homologs thereof. Therapeutic agents include, but are not limited to,antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine,cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g.,mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin),bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents(e.g., vincristine and vinblastine).

The conjugates of the invention can be used for modifying a givenbiological response, the therapeutic agent or drug moiety is not to beconstrued as limited to classical chemical therapeutic agents. Forexample, the drug moiety may be a protein or polypeptide possessing adesired biological activity. Such proteins may include, for example, atoxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin;a protein such as tumor necrosis factor, a-interferon, β-interferon,nerve growth factor, platelet derived growth factor, tissue plasminogenactivator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See,International Publication No. WO 97/33899), AIM II (See, InternationalPublication No. WO 97/34911), Fas Ligand (Takahashi et al., Int.Immunol., 6:1567-1574 (1994)), VEGI (See, International Publication No.WO 99/23105), a thrombotic agent or an anti-angiogenic agent, e.g.,angiostatin or endostatin; or, biological response modifiers such as,for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2(“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colonystimulating factor (“GM-CSF”), granulocyte colony stimulating factor(“G-CSF”), or other growth factors.

Antibodies may also be attached to solid supports, which areparticularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride orpolypropylene.

Techniques for conjugating such therapeutic moiety to antibodies arewell known. See, for example, Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “ThePreparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol. Rev. 62:119-58 (1982).

Alternatively, an antibody can be conjugated to a second antibody toform an antibody heteroconjugate as described by Segal in U.S. Pat. No.4,676,980, which is incorporated herein by reference in its entirety.

An antibody, with or without a therapeutic moiety conjugated to it,administered alone or in combination with cytotoxic factor(s) and/orcytokine(s) can be used as a therapeutic.

Immunophenotyping

The antibodies of the invention may be utilized for immunophenotyping ofcell lines and biological samples. Translation products of the gene ofthe present invention may be useful as cell-specific markers, or morespecifically as cellular markers that are differentially expressed atvarious stages of differentiation and/or maturation of particular celltypes. Monoclonal antibodies directed against a specific epitope, orcombination of epitopes, will allow for the screening of cellularpopulations expressing the marker. Various techniques can be utilizedusing monoclonal antibodies to screen for cellular populationsexpressing the marker(s), and include magnetic separation usingantibody-coated magnetic beads, “panning” with antibody attached to asolid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No.5,985,660; and Morrison et al., Cell, 96:737-49 (1999)).

These techniques allow for the screening of particular populations ofcells, such as might be found with hematological malignancies (i.e.minimal residual disease (MRD) in acute leukemic patients) and“non-self” cells in transplantations to prevent Graft-versus-HostDisease (GVHD). Alternatively, these techniques allow for the screeningof hematopoietic stem and progenitor cells capable of undergoingproliferation and/or differentiation, as might be found in humanumbilical cord blood.

Assays for Antibody Binding

The antibodies of the invention may be assayed for immunospecificbinding by any method known in the art. The immunoassays which can beused include but are not limited to competitive and non-competitiveassay systems using techniques such as western blots, radioimmunoassays,ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays,immunoprecipitation assays, precipitin reactions, gel diffusionprecipitin reactions, immunodiffusion assays, agglutination assays,complement-fixation assays, immunoradiometric assays, fluorescentimmunoassays, and protein A immunoassays, to name but a few. Such assaysare routine and well known in the art (see, e.g., Ausubel et al, eds,1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons,Inc., New York, which is incorporated by reference herein in itsentirety). Exemplary immunoassays are described briefly below (but arenot intended by way of limitation).

Immunoprecipitation protocols generally comprise lysing a population ofcells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100,1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphateat pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/orprotease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate),adding the antibody of interest to the cell lysate, incubating for aperiod of time (e.g., 1-4 hours) at 4° C., adding protein A and/orprotein G sepharose beads to the cell lysate, incubating for about anhour or more at 4° C., washing the beads in lysis buffer andresuspending the beads in SDS/sample buffer. The ability of the antibodyof interest to immunoprecipitate a particular antigen can be assessedby, e.g., western blot analysis. One of skill in the art would beknowledgeable as to the parameters that can be modified to increase thebinding of the antibody to an antigen and decrease the background (e.g.,pre-clearing the cell lysate with sepharose beads). For furtherdiscussion regarding immunoprecipitation protocols see, e.g., Ausubel etal., eds., (1994), Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York, section 10.16.1.

Western blot analysis generally comprises preparing protein samples,electrophoresis of the protein samples in a polyacrylamide gel (e.g.,8%-20% SDS-PAGE depending on the molecular weight of the antigen),transferring the protein sample from the polyacrylamide gel to amembrane such as nitrocellulose, PVDF or nylon, blocking the membrane inblocking solution (e.g., PBS with 3% BSA or non-fat milk), washing themembrane in washing buffer (e.g., PBS-Tween 20), blocking the membranewith primary antibody (the antibody of interest) diluted in blockingbuffer, washing the membrane in washing buffer, blocking the membranewith a secondary antibody (which recognizes the primary antibody, e.g.,an anti-human antibody) conjugated to an enzymatic substrate (e.g.,horseradish peroxidase or alkaline phosphatase) or radioactive molecule(e.g., 32P or 125I) diluted in blocking buffer, washing the membrane inwash buffer, and detecting the presence of the antigen. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the signal detected and to reduce the background noise. Forfurther discussion regarding western blot protocols see, e.g., Ausubelet al, eds, (1994), Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York, section 10.8.1.

ELISAs comprise preparing antigen, coating the well of a 96 wellmicrotiter plate with the antigen, adding the antibody of interestconjugated to a detectable compound such as an enzymatic substrate(e.g., horseradish peroxidase or alkaline phosphatase) to the well andincubating for a period of time, and detecting the presence of theantigen. In ELISAs the antibody of interest does not have to beconjugated to a detectable compound; instead, a second antibody (whichrecognizes the antibody of interest) conjugated to a detectable compoundmay be added to the well. Further, instead of coating the well with theantigen, the antibody may be coated to the well. In this case, a secondantibody conjugated to a detectable compound may be added following theaddition of the antigen of interest to the coated well. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the signal detected as well as other variations of ELISAsknown in the art. For further discussion regarding ELISAs see, e.g.,Ausubel et al, eds, (1994), Current Protocols in Molecular Biology, Vol.1, John Wiley & Sons, Inc., New York, section 11.2.1.

The binding affinity of an antibody to an antigen and the off-rate of anantibody-antigen interaction can be determined by competitive bindingassays. One example of a competitive binding assay is a radioimmunoassaycomprising the incubation of labeled antigen (e.g., 3H or 125I) with theantibody of interest in the presence of increasing amounts of unlabeledantigen, and the detection of the antibody bound to the labeled antigen.The affinity of the antibody of interest for a particular antigen andthe binding off-rates can be determined from the data by scatchard plotanalysis. Competition with a second antibody can also be determinedusing radioimmunoassays. In this case, the antigen is incubated withantibody of interest conjugated to a labeled compound (e.g., 3H or 125I)in the presence of increasing amounts of an unlabeled second antibody.

Antibodies of the invention may be characterized usingimmunocytochemisty methods on cells (e.g., mammalian cells, such as CHOcells) transfected with a vector enabling the expression of an antigenor with vector alone using techniques commonly known in the art.Antibodies that bind antigen transfected cells, but not vector-onlytransfected cells, are antigen specific.

Therapeutic Uses

Table 1D: In preferred embodiments, the present invention encompasses amethod of treating a disease or disorder listed in the “PreferredIndications” column of Table 1D; comprising administering to a patientin which such treatment, prevention, or amelioration is desired aprotein, nucleic acid, or antibody of the invention (or fragment orvariant thereof) represented by Table 1A and Table 1D (in the same rowas the disease or disorder to be treated is listed in the “PreferredIndications” column of Table 1D) in an amount effective to treat,prevent, or ameliorate the disease or disorder.

As indicated in Table 1D, the polynucleotides, polypeptides, agonists,or antagonists of the present invention (including antibodies) can beused in assays to test for one or more biological activities. If thesepolynucleotides and polypeptides do exhibit activity in a particularassay, it is likely that these molecules may be involved in the diseasesassociated with the biological activity. Thus, the polynucleotides orpolypeptides, or agonists or antagonists thereof (including antibodies)could be used to treat the associated disease.

The present invention encompasses methods of preventing, treating,diagnosing, or ameliorating a disease or disorder. In preferredembodiments, the present invention encompasses a method of treating adisease or disorder listed in the “Preferred Indications” column ofTable 1D; comprising administering to a patient in which such treatment,prevention, or amelioration is desired a protein, nucleic acid, orantibody of the invention (or fragment or variant thereof) in an amounteffective to treat, prevent, diagnose, or ameliorate the disease ordisorder. The first and seccond columns of Table 1D show the “Gene No.”and “cDNA Clone ID No.”, respectively, indicating certain nucleic acidsand proteins (or antibodies against the same) of the invention(including polynucleotide, polypeptide, and antibody fragments orvariants thereof) that may be used in preventing, treating, diagnosing,or ameliorating the disease(s) or disorder(s) indicated in thecorresponding row in Column 3 of Table 1D.

In another embodiment, the present invention also encompasses methods ofpreventing, treating, diagnosing, or ameliorating a disease or disorderlisted in the “Preferred Indications” column of Table 1D; comprisingadministering to a patient combinations of the proteins, nucleic acids,or antibodies of the invention (or fragments or variants thereof),sharing similar indications as shown in the corresponding rows in Column3 of Table 1D.

The “Preferred Indication” column describes diseases, disorders, and/orconditions that may be treated, prevented, diagnosed, or ameliorated bya protein, nucleic acid, or antibody of the invention (or fragment orvariant thereof).

The recitation of “Cancer” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof) maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g.,leukemias, cancers, and/or as described below under “HyperproliferativeDisorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cancer” recitationin the “Preferred Indication” column of Table 1 D may be used forexample, to diagnose, treat, prevent, and/or ameliorate a neoplasmlocated in a tissue selected from the group consisting of: colon,abdomen, bone, breast, digestive system, liver, pancreas, prostate,peritoneum, lung, blood (e.g., leukemia), endocrine glands (adrenal,parathyroid, pituitary, testicles, ovary, thymus, thyroid), uterus, eye,head and neck, nervous (central and peripheral), lymphatic system,pelvic, skin, soft tissue, spleen, thoracic, and urogenital.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cancer” recitationin the “Preferred Indication” column of Table 1D, may be used forexample, to diagnose, treat, prevent, and/or ameliorate a pre-neoplasticcondition, selected from the group consisting of: hyperplasia (e.g.,endometrial hyperplasia and/or as described in the section entitled“Hyperproliferative Disorders”), metaplasia (e.g., connective tissuemetaplasia, atypical metaplasia, and/or as described in the sectionentitled “Hyperproliferative Disorders”), and/or dysplasia (e.g.,cervical dysplasia, and bronchopulmonary dysplasia).

In another specific embodiment, a protein, nucleic acid, or antibody ofthe invention (or fragment or variant thereof) having a “Cancer”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a benigndysproliferative disorder selected from the group consisting of: benigntumors, fibrocystic conditions, tissue hypertrophy, and/or as describedin the section entitled “Hyperproliferative Disorders”.

The recitation of “Immune/Hematopoietic” in the “Preferred Indication”column indicates that the corresponding nucleic acid and protein, orantibody against the same, of the invention (or fragment or variantthereof), may be used for example, to diagnose, treat, prevent, and/orameliorate diseases and/or disorders relating to neoplastic diseases(e.g., as described below under “Hyperproliferative Disorders”), blooddisorders (e.g., as described below under “Immune Activity”“Cardiovascular Disorders” and/or “Blood-Related Disorders”), andinfections (e.g., as described below under “Infectious Disease”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having the“Immune/Hematopoietic” recitation in the “Preferred Indication” columnof Table 1D, may be used for example, to diagnose, treat, prevent,and/or ameliorate a disease or disorder selected from the groupconsisting of: anemia, pancytopenia, leukopenia, thrombocytopenia,leukemias, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocyticanemia (ALL), plasmacytomas, multiple myeloma, Burkitt's lymphoma,arthritis, asthma, AIDS, autoimmune disease, rheumatoid arthritis,granulomatous disease, immune deficiency, inflammatory bowel disease,sepsis, neutropenia, neutrophilia, psoriasis, immune reactions totransplanted organs and tissues, systemic lupus erythematosis,hemophilia, hypercoagulation, diabetes mellitus, endocarditis,meningitis, Lyme Disease, and allergies.

The recitation of “Reproductive” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe reproductive system (e.g., as described below under “ReproductiveSystem Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Reproductive”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cryptorchism,prostatitis, inguinal hernia, varicocele, leydig cell tumors, verrucouscarcinoma, prostatitis, malacoplakia, Peyronie's disease, penilecarcinoma, squamous cell hyperplasia, dysmenorrhea, ovarianadenocarcinoma, Turner's syndrome, mucopurulent cervicitis,Sertoli-leydig tumors, ovarian cancer, uterine cancer, pelvicinflammatory disease, testicular cancer, prostate cancer, Klinefelter'ssyndrome, Young's syndrome, premature ejaculation, diabetes mellitus,cystic fibrosis, Kartagener's syndrome, testicular atrophy, testicularfeminization, anorchia, ectopic testis, epididymitis, orchitis,gonorrhea, syphilis, testicular torsion, vasitis nodosa, germ celltumors, stromal tumors, dysmenorrhea, retroverted uterus, endometriosis,fibroids, adenomyosis, anovulatory bleeding, amenorrhea, Cushing'ssyndrome, hydatidiform moles, Asherman's syndrome, premature menopause,precocious puberty, uterine polyps, dysfunctional uterine bleeding,cervicitis, chronic cervicitis, mucopurulent cervicitis, cervicaldysplasia, cervical polyps, Nabothian cysts, cervical erosion, cervicalincompetence, cervical neoplasms, pseudohermaphroditism, andpremenstrual syndrome.

The recitation of “Musculoskeletal” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe immune system (e.g., as described below under “Immune Activity”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Musculoskeletal”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: bone cancers (e.g.,osteochondromas, benign chondromas, chondroblastoma, chondromyxoidfibromas, osteoid osteomas, giant cell tumors, multiple myeloma,osteosarcomas), Paget's Disease, rheumatoid arthritis, systemic lupuserythematosus, osteomyelitis, Lyme Disease, gout, bursitis, tendonitis,osteoporosis, osteoarthritis, muscular dystrophy, mitochondrialmyopathy, cachexia, and multiple sclerosis.

The recitation of “Cardiovascular” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”), and disorders ofthe cardiovascular system (e.g., as described below under“Cardiovascular Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Cardiovascular”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: myxomas, fibromas,rhabdomyomas, cardiovascular abnormalities (e.g., congenital heartdefects, cerebral arteriovenous malformations, septal defects), heartdisease (e.g., heart failure, congestive heart disease, arrhythmia,tachycardia, fibrillation, pericardial Disease, endocarditis), cardiacarrest, heart valve disease (e.g., stenosis, regurgitation, prolapse),vascular disease (e.g., hypertension, coronary artery disease, angina,aneurysm, arteriosclerosis, peripheral vascular disease), hyponatremia,hypernatremia, hypokalemia, and hyperkalemia.

The recitation of “Mixed Fetal” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Mixed Fetal”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: spina bifida,hydranencephaly, neurofibromatosis, fetal alcohol syndrome, diabetesmellitus, PKU, Down's syndrome, Patau syndrome, Edwards syndrome, Turnersyndrome, Apert syndrome, Carpenter syndrome, Conradi syndrome, Crouzonsyndrome, cutis laxa, Cornelia de Lange syndrome, Ellis-van Creveldsyndrome, Holt-Oram syndrome, Kartagener syndrome, Meckel-Grubersyndrome, Noonan syndrome, Pallister-Hall syndrome, Rubinstein-Taybisyndrome, Scimitar syndrome, Smith-Lemli-Opitz syndrome,thromocytopenia-absent radius (TAR) syndrome, Treacher Collins syndrome,Williams syndrome, Hirschsprung's disease, Meckel's diverticulum,polycystic kidney disease, Turner's syndrome, and gonadal dysgenesis,Klippel-Feil syndrome, Ostogenesis imperfecta, muscular dystrophy,Tay-Sachs disease, Wilm's tumor, neuroblastoma, and retinoblastoma.

The recitation of “Excretory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and renaldisorders (e.g., as described below under “Renal Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Excretory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: bladder cancer, prostatecancer, benign prostatic hyperplasia, bladder disorders (e.g., urinaryincontinence, urinary retention, urinary obstruction, urinary tractInfections, interstitial cystitis, prostatitis, neurogenic bladder,hematuria), renal disorders (e.g., hydronephrosis, proteinuria, renalfailure, pyelonephritis, urolithiasis, reflux nephropathy, andunilateral obstructive uropathy).

The recitation of “Neural/Sensory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the nervous system (e.g., as described below under “NeuralActivity and Neurological Diseases”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Neural/Sensory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: brain cancer (e.g.,brain stem glioma, brain tumors, central nervous system (Primary)lymphoma, central nervous system lymphoma, cerebellar astrocytoma, andcerebral astrocytoma, neurodegenerative disorders (e.g., Alzheimer'sDisease, Creutzfeldt-Jakob Disease, Parkinson's Disease, and IdiopathicPresenile Dementia), encephalomyelitis, cerebral malaria, meningitis,metabolic brain diseases (e.g., phenylketonuria and pyruvate carboxylasedeficiency), cerebellar ataxia, ataxia telangiectasia, and AIDS DementiaComplex, schizophrenia, attention deficit disorder, hyperactiveattention deficit disorder, autism, and obsessive compulsive disorders.

The recitation of “Respiratory” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the respiratory system (e.g., as described below under“Respiratory Disorders”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Respiratory”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cancers of therespiratory system such as larynx cancer, pharynx cancer, tracheacancer, epiglottis cancer, lung cancer, squamous cell carcinomas, smallcell (oat cell) carcinomas, large cell carcinomas, and adenocarcinomas.Allergic reactions, cystic fibrosis, sarcoidosis, histiocytosis X,infiltrative lung diseases (e.g., pulmonary fibrosis and lymphoidinterstitial pneumonia), obstructive airway diseases (e.g., asthma,emphysema, chronic or acute bronchitis), occupational lung diseases(e.g., silicosis and asbestosis), pneumonia, and pleurisy.

The recitation of “Endocrine” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the respiratory system (e.g., as described below under“Respiratory Disorders”), renal disorders (e.g., as described belowunder “Renal Disorders”), and disorders of the endocrine system (e.g.,as described below under “Endocrine Disorders”.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having an “Endocrine”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: cancers of endocrinetissues and organs (e.g., cancers of the hypothalamus, pituitary gland,thyroid gland, parathyroid glands, pancreas, adrenal glands, ovaries,and testes), diabetes (e.g., diabetes insipidus, type I and type IIdiabetes mellitus), obesity, disorders related to pituitary glands(e.g., hyperpituitarism, hypopituitarism, and pituitary dwarfism),hypothyroidism, hyperthyroidism, goiter, reproductive disorders (e.g.male and female infertility), disorders related to adrenal glands (e.g.,Addison's Disease, corticosteroid deficiency, and Cushing's Syndrome),kidney cancer (e.g., hypemephroma, transitional cell cancer, and Wilm'stumor), diabetic nephropathy, interstitial nephritis, polycystic kidneydisease, glomerulonephritis (e.g., IgM mesangial proliferativeglomerulonephritis and glomerulonephritis caused by autoimmunedisorders; such as Goodpasture's syndrome), and nephrocalcinosis.

The recitation of “Digestive” in the “Preferred Indication” columnindicates that the corresponding nucleic acid and protein, or antibodyagainst the same, of the invention (or fragment or variant thereof), maybe used for example, to diagnose, treat, prevent, and/or amelioratediseases and/or disorders relating to neoplastic diseases (e.g., asdescribed below under “Hyperproliferative Disorders”) and diseases ordisorders of the gastrointestinal system (e.g., as described below under“Gastrointestinal Disorders”.

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a “Digestive”recitation in the “Preferred Indication” column of Table 1D, may be usedfor example, to diagnose, treat, prevent, and/or ameliorate a disease ordisorder selected from the group consisting of: ulcerative colitis,appendicitis, Crohn's disease, hepatitis, hepatic encephalopathy, portalhypertension, cholelithiasis, cancer of the digestive system (e.g.,biliary tract cancer, stomach cancer, colon cancer, gastric cancer,pancreatic cancer, cancer of the bile duct, tumors of the colon (e.g.,polyps or cancers), and cirrhosis), pancreatitis, ulcerative disease,pyloric stenosis, gastroenteritis, gastritis, gastric atropy, benigntumors of the duodenum, distension, irritable bowel syndrome,malabsorption, congenital disorders of the small intestine, bacterialand parasitic infection, megacolon, Hirschsprung's disease, aganglionicmegacolon, acquired megacolon, colitis, anorectal disorders (e.g., analfistulas, hemorrhoids), congenital disorders of the liver (e.g.,Wilson's disease, hemochromatosis, cystic fibrosis, biliary atresia, andalpha1-antitrypsin deficiency), portal hypertension, cholelithiasis, andjaundice.

The recitation of “Connective/Epithelial” in the “Preferred Indication”column indicates that the corresponding nucleic acid and protein, orantibody against the same, of the invention (or fragment or variantthereof), may be used for example, to diagnose, treat, prevent, and/orameliorate diseases and/or disorders relating to neoplastic diseases(e.g., as described below under “Hyperproliferative Disorders”),cellular and genetic abnormalities (e.g., as described below under“Diseases at the Cellular Level”), angiogenesis (e.g., as describedbelow under “Anti-Angiogenesis Activity”), and or to promote or inhibitregeneration (e.g., as described below under “Regeneration”), and woundhealing (e.g., as described below under “Wound Healing and EpithelialCell Proliferation”).

In specific embodiments, a protein, nucleic acid, or antibody of theinvention (or fragment or variant thereof) having a“Connective/Epithelial” recitation in the “Preferred Indication” columnof Table 1D, may be used for example, to diagnose, treat, prevent,and/or ameliorate a disease or disorder selected from the groupconsisting of: connective tissue metaplasia, mixed connective tissuedisease, focal epithelial hyperplasia, epithelial metaplasia,mucoepithelial dysplasia, graft v. host disease, polymyositis, cystichyperplasia, cerebral dysplasia, tissue hypertrophy, Alzheimer'sdisease, lymphoproliferative disorder, Waldenstron's macroglobulinemia,Crohn's disease, pernicious anemia, idiopathic Addison's disease,glomerulonephritis, bullous pemphigoid, Sjogren's syndrome, diabetesmellitus, cystic fibrosis, osteoblastoma, osteoclastoma, osteosarcoma,chondrosarcoma, osteoporosis, osteocarthritis, periodontal disease,wound healing, relapsing polychondritis, vasculitis, polyarteritisnodosa, Wegener's granulomatosis, cellulitis, rheumatoid arthritis,psoriatic arthritis, discoid lupus erythematosus, systemic lupuserythematosus, scleroderma, CREST syndrome, Sjogren's syndrome,polymyositis, dermatomyositis, mixed connective tissue disease,relapsing polychondritis, vasculitis, Henoch-Schonlein syndrome,erythema nodosum, polyarteritis nodosa, temporal (giant cell) arteritis,Takayasu's arteritis, Wegener's granulomatosis, Reiter's syndrome,Behcet's syndrome, ankylosing spondylitis, cellulitis, keloids, EhlerDanlos syndrome, Marfan syndrome, pseudoxantoma elasticum, osteogeneseimperfecta, chondrodysplasias, epidermolysis bullosa, Alport syndrome,and cutis laxa.

Table 1E also provides information regarding biological activities andpreferred therapeutic uses (i.e. see, “Preferred Indications” column)for polynucleotides and polypeptides of the invention (includingantibodies, agonists, and/or antagonists thereof). Table 1E alsoprovides information regarding assays which may be used to testpolynucleotides and polypeptides of the invention (including antibodies,agonists, and/or antagonists thereof) for the corresponding biologicalactivities. The first column (“Gene No.”) provides the gene number inthe application for each clone identifier. The second column (“cDNA ATCCDeposit No: Z”) provides the unique clone identifier for each clone aspreviously described and indicated in Tables 1A, 1B, 1C, and 1D. Thethird column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ IDNumber for polypeptide sequences encoded by the corresponding cDNAclones (also as indicated in Tables 1A, 1B, and 2). The fourth column(“Biological Activity”) indicates a biological activity corresponding tothe indicated polypeptides (or polynucleotides encoding saidpolypeptides). The fifth column (“Exemplary Activity Assay”) furtherdescribes the corresponding biological activity and also providesinformation pertaining to the various types of assays which may beperformed to test, demonstrate, or quantify the corresponding biologicalactivity. The sixth column (“Preferred Indications”) describesparticular embodiments of the invention as well as indications (e.g.pathologies, diseases, disorders, abnormalities, etc.) for whichpolynucleotides and polypeptides of the invention (including antibodies,agonists, and/or antagonists thereof) may be used in detecting,diagnosing, preventing, and/or treating.

The present invention is further directed to antibody-based therapieswhich involve administering antibodies of the invention to an animal,preferably a mammal, and most preferably a human, patient for treatingone or more of the disclosed diseases, disorders, or conditions.Therapeutic compounds of the invention include, but are not limited to,antibodies of the invention (including fragments, analogs andderivatives thereof as described herein) and nucleic acids encodingantibodies of the invention (including fragments, analogs andderivatives thereof and anti-idiotypic antibodies as described herein).The antibodies of the invention can be used to treat, inhibit or preventdiseases, disorders or conditions associated with aberrant expressionand/or activity of a polypeptide of the invention, including, but notlimited to, any one or more of the diseases, disorders, or conditionsdescribed herein. The treatment and/or prevention of diseases,disorders, or conditions associated with aberrant expression and/oractivity of a polypeptide of the invention includes, but is not limitedto, alleviating symptoms associated with those diseases, disorders orconditions. Antibodies of the invention may be provided inpharmaceutically acceptable compositions as known in the art or asdescribed herein.

In a specific and preferred embodiment, the present invention isdirected to antibody-based therapies which involve administeringantibodies of the invention to an animal, preferably a mammal, and mostpreferably a human, patient for treating one or more diseases,disorders, or conditions, including but not limited to: neuraldisorders, immune system disorders, muscular disorders, reproductivedisorders, gastrointestinal disorders, pulmonary disorders,cardiovascular disorders, renal disorders, proliferative disorders,and/or cancerous diseases and conditions., and/or as described elsewhereherein. Therapeutic compounds of the invention include, but are notlimited to, antibodies of the invention (e.g., antibodies directed tothe full length protein expressed on the cell surface of a mammaliancell; antibodies directed to an epitope of a polypeptide of theinvention (such as, for example, a predicted linear epitope shown incolumn 7 of Table 1B.1; or a conformational epitope, includingfragments, analogs and derivatives thereof as described herein) andnucleic acids encoding antibodies of the invention (including fragments,analogs and derivatives thereof and anti-idiotypic antibodies asdescribed herein). The antibodies of the invention can be used to treat,inhibit or prevent diseases, disorders or conditions associated withaberrant expression and/or activity of a polypeptide of the invention,including, but not limited to, any one or more of the diseases,disorders, or conditions described herein. The treatment and/orprevention of diseases, disorders, or conditions associated withaberrant expression and/or activity of a polypeptide of the inventionincludes, but is not limited to, alleviating symptoms associated withthose diseases, disorders or conditions. Antibodies of the invention maybe provided in pharmaceutically acceptable compositions as known in theart or as described herein.

A summary of the ways in which the antibodies of the present inventionmay be used therapeutically includes binding polynucleotides orpolypeptides of the present invention locally or systemically in thebody or by direct cytotoxicity of the antibody, e.g. as mediated bycomplement (CDC) or by effector cells (ADCC). Some of these approachesare described in more detail below. Armed with the teachings providedherein, one of ordinary skill in the art will know how to use theantibodies of the present invention for diagnostic, monitoring ortherapeutic purposes without undue experimentation.

The antibodies of this invention may be advantageously utilized incombination with other monoclonal or chimeric antibodies, or withlymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3and IL-7), for example, which serve to increase the number or activityof effector cells which interact with the antibodies.

The antibodies of the invention may be administered alone or incombination with other types of treatments (e.g., radiation therapy,chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents).Generally, administration of products of a species origin or speciesreactivity (in the case of antibodies) that is the same species as thatof the patient is preferred. Thus, in a preferred embodiment, humanantibodies, fragments derivatives, analogs, or nucleic acids, areadministered to a human patient for therapy or prophylaxis.

It is preferred to use high affinity and/or potent in vivo inhibitingand/or neutralizing antibodies against polypeptides or polynucleotidesof the present invention, fragments or regions thereof, for bothimmunoassays directed to and therapy of disorders related topolynucleotides or polypeptides, including fragments thereof, of thepresent invention. Such antibodies, fragments, or regions, willpreferably have an affinity for polynucleotides or polypeptides of theinvention, including fragments thereof. Preferred binding affinitiesinclude those with a dissociation constant or Kd less than 5×10⁻² M,10⁻² M, 5×10⁻³ M, 10⁻³M, 5×10⁻⁴ M, 10⁻⁴ M, 5×10⁻⁵ M, 10⁻⁵ M, 5×10⁻⁶ M,10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰ M,10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³ M, 10⁻¹³ M,5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, and 10⁻¹⁵ M.

Gene Therapy

In a specific embodiment, nucleic acids comprising sequences encodingantibodies or functional derivatives thereof, are administered to treat,inhibit or prevent a disease or disorder associated with aberrantexpression and/or activity of a polypeptide of the invention, by way ofgene therapy. Gene therapy refers to therapy performed by theadministration to a subject of an expressed or expressible nucleic acid.In this embodiment of the invention, the nucleic acids produce theirencoded protein that mediates a therapeutic effect.

Any of the methods for gene therapy available in the art can be usedaccording to the present invention. Exemplary methods are describedbelow.

For general reviews of the methods of gene therapy, see Goldspiel etal., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy 3:87-95(1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993);Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev.Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993). Methodscommonly known in the art of recombinant DNA technology which can beused are described in Ausubel et al. (eds.), Current Protocols inMolecular Biology, John Wiley & Sons, NY (1993); and Kriegler, GeneTransfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).

In a preferred embodiment, the compound comprises nucleic acid sequencesencoding an antibody, said nucleic acid sequences being part ofexpression vectors that express the antibody or fragments or chimericproteins or heavy or light chains thereof in a suitable host. Inparticular, such nucleic acid sequences have promoters operably linkedto the antibody coding region, said promoter being inducible orconstitutive, and, optionally, tissue-specific. In another particularembodiment, nucleic acid molecules are used in which the antibody codingsequences and any other desired sequences are flanked by regions thatpromote homologous recombination at a desired site in the genome, thusproviding for intrachromosomal expression of the antibody encodingnucleic acids (Koller and Smithies, Proc. Natl. Acad. Sci. USA86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989). Inspecific embodiments, the expressed antibody molecule is a single chainantibody; alternatively, the nucleic acid sequences include sequencesencoding both the heavy and light chains, or fragments thereof, of theantibody.

Delivery of the nucleic acids into a patient may be either direct, inwhich case the patient is directly exposed to the nucleic acid ornucleic acid-carrying vectors, or indirect, in which case, cells arefirst transformed with the nucleic acids in vitro, then transplantedinto the patient. These two approaches are known, respectively, as invivo or ex vivo gene therapy.

In a specific embodiment, the nucleic acid sequences are directlyadministered in vivo, where it is expressed to produce the encodedproduct. This can be accomplished by any of numerous methods known inthe art, e.g., by constructing them as part of an appropriate nucleicacid expression vector and administering it so that they becomeintracellular, e.g., by infection using defective or attenuatedretrovirals or other viral vectors (see U.S. Pat. No. 4,980,286), or bydirect injection of naked DNA, or by use of microparticle bombardment(e.g., a gene gun; Biolistic, Dupont), or coating with lipids orcell-surface receptors or transfecting agents, encapsulation inliposomes, microparticles, or microcapsules, or by administering them inlinkage to a peptide which is known to enter the nucleus, byadministering it in linkage to a ligand subject to receptor-mediatedendocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987))(which can be used to target cell types specifically expressing thereceptors), etc. In another embodiment, nucleic acid-ligand complexescan be formed in which the ligand comprises a fusogenic viral peptide todisrupt endosomes, allowing the nucleic acid to avoid lysosomaldegradation. In yet another embodiment, the nucleic acid can be targetedin vivo for cell specific uptake and expression, by targeting a specificreceptor (see, e.g., PCT Publications WO 92/06180; WO 92/22635;WO92/20316; WO93/14188, WO 93/20221). Alternatively, the nucleic acidcan be introduced intracellularly and incorporated within host cell DNAfor expression, by homologous recombination (Koller and Smithies, Proc.Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature342:435-438 (1989)).

In a specific embodiment, viral vectors that contains nucleic acidsequences encoding an antibody of the invention are used. For example, aretroviral vector can be used (see Miller et al., Meth. Enzymol.217:581-599 (1993)). These retroviral vectors contain the componentsnecessary for the correct packaging of the viral genome and integrationinto the host cell DNA. The nucleic acid sequences encoding the antibodyto be used in gene therapy are cloned into one or more vectors, whichfacilitates delivery of the gene into a patient. More detail aboutretroviral vectors can be found in Boesen et al., Biotherapy 6:291-302(1994), which describes the use of a retroviral vector to deliver themdr1 gene to hematopoietic stem cells in order to make the stem cellsmore resistant to chemotherapy. Other references illustrating the use ofretroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest.93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons andGunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson,Curr. Opin. in Genetics and Devel. 3:110-114 (1993).

Adenoviruses are other viral vectors that can be used in gene therapy.Adenoviruses are especially attractive vehicles for delivering genes torespiratory epithelia. Adenoviruses naturally infect respiratoryepithelia where they cause a mild disease. Other targets foradenovirus-based delivery systems are liver, the central nervous system,endothelial cells, and muscle. Adenoviruses have the advantage of beingcapable of infecting non-dividing cells. Kozarsky and Wilson, CurrentOpinion in Genetics and Development 3:499-503 (1993) present a review ofadenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10(1994) demonstrated the use of adenovirus vectors to transfer genes tothe respiratory epithelia of rhesus monkeys. Other instances of the useof adenoviruses in gene therapy can be found in Rosenfeld et al.,Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992);Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT PublicationWO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). In apreferred embodiment, adenovirus vectors are used.

Adeno-associated virus (AAV) has also been proposed for use in genetherapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993);U.S. Pat. No. 5,436,146).

Another approach to gene therapy involves transferring a gene to cellsin tissue culture by such methods as electroporation, lipofection,calcium phosphate mediated transfection, or viral infection. Usually,the method of transfer includes the transfer of a selectable marker tothe cells. The cells are then placed under selection to isolate thosecells that have taken up and are expressing the transferred gene. Thosecells are then delivered to a patient.

In this embodiment, the nucleic acid is introduced into a cell prior toadministration in vivo of the resulting recombinant cell. Suchintroduction can be carried out by any method known in the art,including but not limited to transfection, electroporation,microinjection, infection with a viral or bacteriophage vectorcontaining the nucleic acid sequences, cell fusion, chromosome-mediatedgene transfer, microcell-mediated gene transfer, spheroplast fusion,etc. Numerous techniques are known in the art for the introduction offoreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol.217:599-618 (1993); Cohen et al., Meth. Enzymol. 217:618-644 (1993);Cline, Pharmac. Ther. 29:69-92m (1985) and may be used in accordancewith the present invention, provided that the necessary developmentaland physiological functions of the recipient cells are not disrupted.The technique should provide for the stable transfer of the nucleic acidto the cell, so that the nucleic acid is expressible by the cell andpreferably heritable and expressible by its cell progeny.

The resulting recombinant cells can be delivered to a patient by variousmethods known in the art. Recombinant blood cells (e.g., hematopoieticstem or progenitor cells) are preferably administered intravenously. Theamount of cells envisioned for use depends on the desired effect,patient state, etc., and can be determined by one skilled in the art.

Cells into which a nucleic acid can be introduced for purposes of genetherapy encompass any desired, available cell type, and include but arenot limited to epithelial cells, endothelial cells, keratinocytes,fibroblasts, muscle cells, hepatocytes; blood cells such as Tlymphocytes, B lymphocytes, monocytes, macrophages, neutrophils,eosinophils, megakaryocytes, granulocytes; various stem or progenitorcells, in particular hematopoietic stem or progenitor cells, e.g., asobtained from bone marrow, umbilical cord blood, peripheral blood, fetalliver, etc.

In a preferred embodiment, the cell used for gene therapy is autologousto the patient.

In an embodiment in which recombinant cells are used in gene therapy,nucleic acid sequences encoding an antibody are introduced into thecells such that they are expressible by the cells or their progeny, andthe recombinant cells are then administered in vivo for therapeuticeffect. In a specific embodiment, stem or progenitor cells are used. Anystem and/or progenitor cells which can be isolated and maintained invitro can potentially be used in accordance with this embodiment of thepresent invention (see e.g. PCT Publication WO 94/08598; Stemple andAnderson, Cell 71:973-985 (1992); Rheinwald, Meth. Cell Bio. 21A:229(1980); and Pittelkow and Scott, Mayo Clinic Proc. 61:771 (1986)).

In a specific embodiment, the nucleic acid to be introduced for purposesof gene therapy comprises an inducible promoter operably linked to thecoding region, such that expression of the nucleic acid is controllableby the presence or absence of an appropriate inducer of transcription.

Demonstration of Therapeutic or Prophylactic Activity

The compounds or pharmaceutical compositions of the invention arepreferably tested in vitro, and then in vivo for the desired therapeuticor prophylactic activity, prior to use in humans. For example, in vitroassays to demonstrate the therapeutic or prophylactic utility of acompound or pharmaceutical composition include, the effect of a compoundon a cell line or a patient tissue sample. The effect of the compound orcomposition on the cell line and/or tissue sample can be determinedutilizing techniques known to those of skill in the art including, butnot limited to, rosette formation assays and cell lysis assays. Inaccordance with the invention, in vitro assays which can be used todetermine whether administration of a specific compound is indicated,include in vitro cell culture assays in which a patient tissue sample isgrown in culture, and exposed to or otherwise administered a compound,and the effect of such compound upon the tissue sample is observed.

Therapeutic/Prophylactic Administration and Composition

The invention provides methods of treatment, inhibition and prophylaxisby administration to a subject of an effective amount of a compound orpharmaceutical composition of the invention, preferably a polypeptide orantibody of the invention. In a preferred embodiment, the compound issubstantially purified (e.g., substantially free from substances thatlimit its effect or produce undesired side-effects). The subject ispreferably an animal, including but not limited to animals such as cows,pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal,and most preferably human.

Formulations and methods of administration that can be employed when thecompound comprises a nucleic acid or an immunoglobulin are describedabove; additional appropriate formulations and routes of administrationcan be selected from among those described herein below.

Various delivery systems are known and can be used to administer acompound of the invention, e.g., encapsulation in liposomes,microparticles, microcapsules, recombinant cells capable of expressingthe compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J.Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid aspart of a retroviral or other vector, etc. Methods of introductioninclude but are not limited to intradermal, intramuscular,intraperitoneal, intravenous, subcutaneous, intranasal, epidural, andoral routes. The compounds or compositions may be administered by anyconvenient route, for example by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.) and may be administeredtogether with other biologically active agents. Administration can besystemic or local. In addition, it may be desirable to introduce thepharmaceutical compounds or compositions of the invention into thecentral nervous system by any suitable route, including intraventricularand intrathecal injection; intraventricular injection may be facilitatedby an intraventricular catheter, for example, attached to a reservoir,such as an Ommaya reservoir. Pulmonary administration can also beemployed, e.g., by use of an inhaler or nebulizer, and formulation withan aerosolizing agent.

In a specific embodiment, it may be desirable to administer thepharmaceutical compounds or compositions of the invention locally to thearea in need of treatment; this may be achieved by, for example, and notby way of limitation, local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository, or bymeans of an implant, said implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers. Preferably, when administering a protein, including anantibody, of the invention, care must be taken to use materials to whichthe protein does not absorb.

In another embodiment, the compound or composition can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.)

In yet another embodiment, the compound or composition can be deliveredin a controlled release system. In one embodiment, a pump may be used(see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989)). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem.23:61 (1983); see also Levy et al., Science 228:190 (1985); During etal., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105(1989)). In yet another embodiment, a controlled release system can beplaced in proximity of the therapeutic target, e.g., the brain, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson, inMedical Applications of Controlled Release, supra, vol. 2, pp. 115-138(1984)).

Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)).

In a specific embodiment where the compound of the invention is anucleic acid encoding a protein, the nucleic acid can be administered invivo to promote expression of its encoded protein, by constructing it aspart of an appropriate nucleic acid expression vector and administeringit so that it becomes intracellular, e.g., by use of a retroviral vector(see U.S. Pat. No. 4,980,286), or by direct injection, or by use ofmicroparticle bombardment (e.g., a gene gun; Biolistic, Dupont), orcoating with lipids or cell-surface receptors or transfecting agents, orby administering it in linkage to a homeobox-like peptide which is knownto enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci.USA 88:1864-1868 (1991)), etc. Alternatively, a nucleic acid can beintroduced intracellularly and incorporated within host cell DNA forexpression, by homologous recombination.

The present invention also provides pharmaceutical compositions. Suchcompositions comprise a therapeutically effective amount of a compound,and a pharmaceutically acceptable carrier. In a specific embodiment, theterm “pharmaceutically acceptable” means approved by a regulatory agencyof the Federal or a state government or listed in the U.S. Pharmacopeiaor other generally recognized pharmacopeia for use in animals, and moreparticularly in humans. The term “carrier” refers to a diluent,adjuvant, excipient, or vehicle with which the therapeutic isadministered. Such pharmaceutical carriers can be sterile liquids, suchas water and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. Water is a preferred carrier when the pharmaceuticalcomposition is administered intravenously. Saline solutions and aqueousdextrose and glycerol solutions can also be employed as liquid carriers,particularly for injectable solutions. Suitable pharmaceuticalexcipients include starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The composition, if desired, can alsocontain minor amounts of wetting or emulsifying agents, or pH bufferingagents. These compositions can take the form of solutions, suspensions,emulsion, tablets, pills, capsules, powders, sustained-releaseformulations and the like. The composition can be formulated as asuppository, with traditional binders and carriers such astriglycerides. Oral formulation can include standard carriers such aspharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Examples ofsuitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences” by E. W. Martin. Such compositions will containa therapeutically effective amount of the compound, preferably inpurified form, together with a suitable amount of carrier so as toprovide the form for proper administration to the patient. Theformulation should suit the mode of administration.

In a preferred embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

The compounds of the invention can be formulated as neutral or saltforms. Pharmaceutically acceptable salts include those formed withanions such as those derived from hydrochloric, phosphoric, acetic,oxalic, tartaric acids, etc., and those formed with cations such asthose derived from sodium, potassium, ammonium, calcium, ferrichydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, etc.

The amount of the compound of the invention which will be effective inthe treatment, inhibition and prevention of a disease or disorderassociated with aberrant expression and/or activity of a polypeptide ofthe invention can be determined by standard clinical techniques. Inaddition, in vitro assays may optionally be employed to help identifyoptimal dosage ranges. The precise dose to be employed in theformulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided accordingto the judgment of the practitioner and each patient's circumstances.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For antibodies, the dosage administered to a patient is typically 0.1mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosageadministered to a patient is between 0.1 mg/kg and 20 mg/kg of thepatient's body weight, more preferably 1 mg/kg to 10 mg/kg of thepatient's body weight. Generally, human antibodies have a longerhalf-life within the human body than antibodies from other species dueto the immune response to the foreign polypeptides. Thus, lower dosagesof human antibodies and less frequent administration is often possible.Further, the dosage and frequency of administration of antibodies of theinvention may be reduced by enhancing uptake and tissue penetration(e.g., into the brain) of the antibodies by modifications such as, forexample, lipidation.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

Diagnosis and Imaging

Labeled antibodies, and derivatives and analogs thereof, whichspecifically bind to a polypeptide of interest can be used fordiagnostic purposes to detect, diagnose, or monitor diseases, disorders,and/or conditions associated with the aberrant expression and/oractivity of a polypeptide of the invention. The invention provides forthe detection of aberrant expression of a polypeptide of interest,comprising (a) assaying the expression of the polypeptide of interest incells or body fluid of an individual using one or more antibodiesspecific to the polypeptide interest and (b) comparing the level of geneexpression with a standard gene expression level, whereby an increase ordecrease in the assayed polypeptide gene expression level compared tothe standard expression level is indicative of aberrant expression.

The invention provides a diagnostic assay for diagnosing a disorder,comprising (a) assaying the expression of the polypeptide of interest incells or body fluid of an individual using one or more antibodiesspecific to the polypeptide interest and (b) comparing the level of geneexpression with a standard gene expression level, whereby an increase ordecrease in the assayed polypeptide gene expression level compared tothe standard expression level is indicative of a particular disorder.With respect to cancer, the presence of a relatively high amount oftranscript in biopsied tissue from an individual may indicate apredisposition for the development of the disease, or may provide ameans for detecting the disease prior to the appearance of actualclinical symptoms. A more definitive diagnosis of this type may allowhealth professionals to employ preventative measures or aggressivetreatment earlier thereby preventing the development or furtherprogression of the cancer.

Antibodies of the invention can be used to assay protein levels in abiological sample using classical immunohistological methods known tothose of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol.101:976-985 (1985); Jalkanen et al., J. Cell. Biol. 105:3087-3096(1987)). Other antibody-based methods useful for detecting protein geneexpression include immunoassays, such as the enzyme linked immunosorbentassay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assaylabels are known in the art and include enzyme labels, such as, glucoseoxidase; radioisotopes, such as iodine (125I, 121I), carbon (14C),sulfur (35S), tritium (3H), indium (112In), and technetium (99Tc);luminescent labels, such as luminol; and fluorescent labels, such asfluorescein and rhodamine, and biotin.

One facet of the invention is the detection and diagnosis of a diseaseor disorder associated with aberrant expression of a polypeptide ofinterest in an animal, preferably a mammal and most preferably a human.In one embodiment, diagnosis comprises: a) administering (for example,parenterally, subcutaneously, or intraperitoneally) to a subject aneffective amount of a labeled molecule which specifically binds to thepolypeptide of interest; b) waiting for a time interval following theadministering for permitting the labeled molecule to preferentiallyconcentrate at sites in the subject where the polypeptide is expressed(and for unbound labeled molecule to be cleared to background level); c)determining background level; and d) detecting the labeled molecule inthe subject, such that detection of labeled molecule above thebackground level indicates that the subject has a particular disease ordisorder associated with aberrant expression of the polypeptide ofinterest. Background level can be determined by various methodsincluding, comparing the amount of labeled molecule detected to astandard value previously determined for a particular system.

It will be understood in the art that the size of the subject and theimaging system used will determine the quantity of imaging moiety neededto produce diagnostic images. In the case of a radioisotope moiety, fora human subject, the quantity of radioactivity injected will normallyrange from about 5 to 20 millicuries of 99 mTc. The labeled antibody orantibody fragment will then preferentially accumulate at the location ofcells which contain the specific protein. In vivo tumor imaging isdescribed in S. W. Burchiel et al., “Immunopharmacokinetics ofRadiolabeled Antibodies and Their Fragments.” (Chapter 13 in TumorImaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A.Rhodes, eds., Masson Publishing Inc. (1982)).

Depending on several variables, including the type of label used and themode of administration, the time interval following the administrationfor permitting the labeled molecule to preferentially concentrate atsites in the subject and for unbound labeled molecule to be cleared tobackground level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. Inanother embodiment the time interval following administration is 5 to 20days or 5 to 10 days.

In an embodiment, monitoring of the disease or disorder is carried outby repeating the method for diagnosing the disease or disease, forexample, one month after initial diagnosis, six months after initialdiagnosis, one year after initial diagnosis, etc.

Presence of the labeled molecule can be detected in the patient usingmethods known in the art for in vivo scanning. These methods depend uponthe type of label used. Skilled artisans will be able to determine theappropriate method for detecting a particular label. Methods and devicesthat may be used in the diagnostic methods of the invention include, butare not limited to, computed tomography (CT), whole body scan such asposition emission tomography (PET), magnetic resonance imaging (MRI),and sonography.

In a specific embodiment, the molecule is labeled with a radioisotopeand is detected in the patient using a radiation responsive surgicalinstrument (Thurston et al., U.S. Pat. No. 5,441,050). In anotherembodiment, the molecule is labeled with a fluorescent compound and isdetected in the patient using a fluorescence responsive scanninginstrument. In another embodiment, the molecule is labeled with apositron emitting metal and is detected in the patent using positronemission-tomography. In yet another embodiment, the molecule is labeledwith a paramagnetic label and is detected in a patient using magneticresonance imaging (MRI).

Kits

The present invention provides kits that can be used in the abovemethods. In one embodiment, a kit comprises an antibody of theinvention, preferably a purified antibody, in one or more containers. Ina specific embodiment, the kits of the present invention contain asubstantially isolated polypeptide comprising an epitope which isspecifically immunoreactive with an antibody included in the kit.Preferably, the kits of the present invention further comprise a controlantibody which does not react with the polypeptide of interest. Inanother specific embodiment, the kits of the present invention contain ameans for detecting the binding of an antibody to a polypeptide ofinterest (e.g., the antibody may be conjugated to a detectable substratesuch as a fluorescent compound, an enzymatic substrate, a radioactivecompound or a luminescent compound, or a second antibody whichrecognizes the first antibody may be conjugated to a detectablesubstrate).

In another specific embodiment of the present invention, the kit is adiagnostic kit for use in screening serum containing antibodies specificagainst proliferative and/or cancerous polynucleotides and polypeptides.Such a kit may include a control antibody that does not react with thepolypeptide of interest. Such a kit may include a substantially isolatedpolypeptide antigen comprising an epitope which is specificallyimmunoreactive with at least one anti-polypeptide antigen antibody.Further, such a kit includes means for detecting the binding of saidantibody to the antigen (e.g., the antibody may be conjugated to afluorescent compound such as fluorescein or rhodamine which can bedetected by flow cytometry). In specific embodiments, the kit mayinclude a recombinantly produced or chemically synthesized polypeptideantigen. The polypeptide antigen of the kit may also be attached to asolid support.

In a more specific embodiment the detecting means of the above-describedkit includes a solid support to which said polypeptide antigen isattached. Such a kit may also include a non-attached reporter-labeledanti-human antibody. In this embodiment, binding of the antibody to thepolypeptide antigen can be detected by binding of the saidreporter-labeled antibody.

In an additional embodiment, the invention includes a diagnostic kit foruse in screening serum containing antigens of the polypeptide of theinvention. The diagnostic kit includes a substantially isolated antibodyspecifically immunoreactive with polypeptide or polynucleotide antigens,and means for detecting the binding of the polynucleotide or polypeptideantigen to the antibody. In one embodiment, the antibody is attached toa solid support. In a specific embodiment, the antibody may be amonoclonal antibody. The detecting means of the kit may include asecond, labeled monoclonal antibody. Alternatively, or in addition, thedetecting means may include a labeled, competing antigen.

In one diagnostic configuration, test serum is reacted with a solidphase reagent having a surface-bound antigen obtained by the methods ofthe present invention. After binding with specific antigen antibody tothe reagent and removing unbound serum components by washing, thereagent is reacted with reporter-labeled anti-human antibody to bindreporter to the reagent in proportion to the amount of boundanti-antigen antibody on the solid support. The reagent is again washedto remove unbound labeled antibody, and the amount of reporterassociated with the reagent is determined. Typically, the reporter is anenzyme which is detected by incubating the solid phase in the presenceof a suitable fluorometric, luminescent or calorimetric substrate(Sigma, St. Louis, Mo.).

The solid surface reagent in the above assay is prepared by knowntechniques for attaching protein material to solid support material,such as polymeric beads, dip sticks, 96-well plate or filter material.These attachment methods generally include non-specific adsorption ofthe protein to the support or covalent attachment of the protein,typically through a free amine group, to a chemically reactive group onthe solid support, such as an activated carboxyl, hydroxyl, or aldehydegroup. Alternatively, streptavidin coated plates can be used inconjunction with biotinylated antigen(s).

Thus, the invention provides an assay system or kit for carrying outthis diagnostic method. The kit generally includes a support withsurface-bound recombinant antigens, and a reporter-labeled anti-humanantibody for detecting surface-bound anti-antigen antibody.

Uses of the Polynucleotides

Each of the polynucleotides identified herein can be used in numerousways as reagents. The following description should be consideredexemplary and utilizes known techniques.

The polynucleotides of the present invention are useful for chromosomeidentification. There exists an ongoing need to identify new chromosomemarkers, since few chromosome marking reagents, based on actual sequencedata (repeat polymorphisms), are presently available. Each sequence isspecifically targeted to and can hybridize with a particular location onan individual human chromosome, thus each polynucleotide of the presentinvention can routinely be used as a chromosome marker using techniquesknown in the art. Table 1B.1, column 8 provides the chromosome locationof some of the polynucleotides of the invention.

Briefly, sequences can be mapped to chromosomes by preparing PCR primers(preferably at least 15 bp (e.g., 15-25 bp) from the sequences shown inSEQ ID NO:X. Primers can optionally be selected using computer analysisso that primers do not span more than one predicted exon in the genomicDNA. These primers are then used for PCR screening of somatic cellhybrids containing individual human chromosomes. Only those hybridscontaining the human gene corresponding to SEQ ID NO:X will yield anamplified fragment.

Similarly, somatic hybrids provide a rapid method of PCR mapping thepolynucleotides to particular chromosomes. Three or more clones can beassigned per day using a single thermal cycler. Moreover,sublocalization of the polynucleotides can be achieved with panels ofspecific chromosome fragments. Other gene mapping strategies that can beused include in situ hybridization, prescreening with labeledflow-sorted chromosomes, preselection by hybridization to constructchromosome specific-cDNA libraries, and computer mapping techniques(See, e.g., Shuler, Trends Biotechnol 16:456-459 (1998) which is herebyincorporated by reference in its entirety).

Precise chromosomal location of the polynucleotides can also be achievedusing fluorescence in situ hybridization (FISH) of a metaphasechromosomal spread. This technique uses polynucleotides as short as 500or 600 bases; however, polynucleotides 2,000 bp are preferred. For areview of this technique, see Verma et al., “Human Chromosomes: a Manualof Basic Techniques,” Pergamon Press, New York (1988).

For chromosome mapping, the polynucleotides can be used individually (tomark a single chromosome or a single site on that chromosome) or inpanels (for marking multiple sites and/or multiple chromosomes).

Thus, the present invention also provides a method for chromosomallocalization which involves (a) preparing PCR primers from thepolynucleotide sequences in Table 1B and/or Table 2 and SEQ ID NO:X and(b) screening somatic cell hybrids containing individual chromosomes.

The polynucleotides of the present invention would likewise be usefulfor radiation hybrid mapping, HAPPY mapping, and long range restrictionmapping. For a review of these techniques and others known in the art,see, e.g. Dear, “Genome Mapping: A Practical Approach,” IRL Press atOxford University Press, London (1997); Aydin, J. Mol. Med. 77:691-694(1999); Hacia et al., Mol. Psychiatry 3:483-492 (1998); Herrick et al.,Chromosome Res. 7:409-423 (1999); Hamilton et al., Methods Cell Biol.62:265-280 (2000); and/or Ott, J. Hered. 90:68-70 (1999) each of whichis hereby incorporated by reference in its entirety.

Once a polynucleotide has been mapped to a precise chromosomal location,the physical position of the polynucleotide can be used in linkageanalysis. Linkage analysis establishes coinheritance between achromosomal location and presentation of a particular disease. (Diseasemapping data are found, for example, in V. McKusick, MendelianInheritance in Man (available on line through Johns Hopkins UniversityWelch Medical Library)). Column 9 of Table 1B.1 provides an OMIMreference identification number of diseases associated with thecytologic band disclosed in column 8 of Table 1B.1, as determined usingtechniques described herein and by reference to Table 5. Assuming 1megabase mapping resolution and one gene per 20 kb, a cDNA preciselylocalized to a chromosomal region associated with the disease could beone of 50-500 potential causative genes.

Thus, once coinheritance is established, differences in a polynucleotideof the invention and the corresponding gene between affected andunaffected individuals can be examined. First, visible structuralalterations in the chromosomes, such as deletions or translocations, areexamined in chromosome spreads or by PCR. If no structural alterationsexist, the presence of point mutations are ascertained. Mutationsobserved in some or all affected individuals, but not in normalindividuals, indicates that the mutation may cause the disease. However,complete sequencing of the polypeptide and the corresponding gene fromseveral normal individuals is required to distinguish the mutation froma polymorphism. If a new polymorphism is identified, this polymorphicpolypeptide can be used for further linkage analysis.

Furthermore, increased or decreased expression of the gene in affectedindividuals as compared to unaffected individuals can be assessed usingthe polynucleotides of the invention. Any of these alterations (alteredexpression, chromosomal rearrangement, or mutation) can be used as adiagnostic or prognostic marker. Diagnostic and prognostic methods, kitsand reagents encompassed by the present invention are briefly describedbelow and more thoroughly elsewhere herein (see e.g., the sectionslabeled “Antibodies”, “Diagnostic Assays”, and “Methods for DetectingDiseases”).

Thus, the invention also provides a diagnostic method useful duringdiagnosis of a disorder, involving measuring the expression level ofpolynucleotides of the present invention in cells or body fluid from anindividual and comparing the measured gene expression level with astandard level of polynucleotide expression level, whereby an increaseor decrease in the gene expression level compared to the standard isindicative of a disorder. Additional non-limiting examples of diagnosticmethods encompassed by the present invention are more thoroughlydescribed elsewhere herein (see, e.g., Example 12).

In still another embodiment, the invention includes a kit for analyzingsamples for the presence of proliferative and/or cancerouspolynucleotides derived from a test subject. In a general embodiment,the kit includes at least one polynucleotide probe containing anucleotide sequence that will specifically hybridize with apolynucleotide of the invention and a suitable container. In a specificembodiment, the kit includes two polynucleotide probes defining aninternal region of the polynucleotide of the invention, where each probehas one strand containing a 31′mer-end internal to the region. In afurther embodiment, the probes may be useful as primers for polymerasechain reaction amplification.

Where a diagnosis of a related disorder, including, for example,diagnosis of a tumor, has already been made according to conventionalmethods, the present invention is useful as a prognostic indicator,whereby patients exhibiting enhanced or depressed polynucleotide of theinvention expression will experience a worse clinical outcome relativeto patients expressing the gene at a level nearer the standard level.

By “measuring the expression level of polynucleotides of the invention”is intended qualitatively or quantitatively measuring or estimating thelevel of the polypeptide of the invention or the level of the mRNAencoding the polypeptide of the invention in a first biological sampleeither directly (e.g., by determining or estimating absolute proteinlevel or mRNA level) or relatively (e.g., by comparing to thepolypeptide level or mRNA level in a second biological sample).Preferably, the polypeptide level or mRNA level in the first biologicalsample is measured or estimated and compared to a standard polypeptidelevel or mRNA level, the standard being taken from a second biologicalsample obtained from an individual not having the related disorder orbeing determined by averaging levels from a population of individualsnot having a related disorder. As will be appreciated in the art, once astandard polypeptide level or mRNA level is known, it can be usedrepeatedly as a standard for comparison.

By “biological sample” is intended any biological sample obtained froman individual, body fluid, cell line, tissue culture, or other sourcewhich contains polypeptide of the present invention or the correspondingmRNA. As indicated, biological samples include body fluids (such assemen, lymph, vaginal pool, sera, plasma, urine, synovial fluid andspinal fluid) which contain the polypeptide of the present invention,and tissue sources found to express the polypeptide of the presentinvention. Methods for obtaining tissue biopsies and body fluids frommammals are well known in the art. Where the biological sample is toinclude mRNA, a tissue biopsy is the preferred source.

The method(s) provided above may preferably be applied in a diagnosticmethod and/or kits in which polynucleotides and/or polypeptides of theinvention are attached to a solid support. In one exemplary method, thesupport may be a “gene chip” or a “biological chip” as described in U.S.Pat. Nos. 5,837,832, 5,874,219, and 5,856,174. Further, such a gene chipwith polynucleotides of the invention attached may be used to identifypolymorphisms between the isolated polynucleotide sequences of theinvention, with polynucleotides isolated from a test subject. Theknowledge of such polymorphisms (i.e. their location, as well as, theirexistence) would be beneficial in identifying disease loci for manydisorders, such as for example, in neural disorders, immune systemdisorders, muscular disorders, reproductive disorders, gastrointestinaldisorders, pulmonary disorders, digestive disorders, metabolicdisorders, cardiovascular disorders, renal disorders, proliferativedisorders, and/or cancerous diseases and conditions. Such a method isdescribed in U.S. Pat. Nos. 5,858,659 and 5,856,104. The US Patentsreferenced supra are hereby incorporated by reference in their entiretyherein.

The present invention encompasses polynucleotides of the presentinvention that are chemically synthesized, or reproduced as peptidenucleic acids (PNA), or according to other methods known in the art. Theuse of PNAs would serve as the preferred form if the polynucleotides ofthe invention are incorporated onto a solid support, or gene chip. Forthe purposes of the present invention, a peptide nucleic acid (PNA) is apolyamide type of DNA analog and the monomeric units for adenine,guanine, thymine and cytosine are available commercially (PerceptiveBiosystems). Certain components of DNA, such as phosphorus, phosphorusoxides, or deoxyribose derivatives, are not present in PNAs. Asdisclosed by Nielsen et al., Science 254, 1497 (1991); and Egholm etal., Nature 365, 666 (1993), PNAs bind specifically and tightly tocomplementary DNA strands and are not degraded by nucleases. In fact,PNA binds more strongly to DNA than DNA itself does. This is probablybecause there is no electrostatic repulsion between the two strands, andalso the polyamide backbone is more flexible. Because of this, PNA/DNAduplexes bind under a wider range of stringency conditions than DNA/DNAduplexes, making it easier to perform multiplex hybridization. Smallerprobes can be used than with DNA due to the strong binding. In addition,it is more likely that single base mismatches can be determined withPNA/DNA hybridization because a single mismatch in a PNA/DNA 15-merlowers the melting point (T.sub.m) by 8°-20° C., vs. 4°-16° C. for theDNA/DNA 15-mer duplex. Also, the absence of charge groups in PNA meansthat hybridization can be done at low ionic strengths and reducepossible interference by salt during the analysis.

The compounds of the present invention have uses which include, but arenot limited to, detecting cancer in mammals. In particular the inventionis useful during diagnosis of pathological cell proliferative neoplasiaswhich include, but are not limited to: acute myelogenous leukemiasincluding acute monocytic leukemia, acute myeloblastic leukemia, acutepromyelocytic leukemia, acute myelomonocytic leukemia, acuteerythroleukemia, acute megakaryocytic leukemia, and acuteundifferentiated leukemia, etc.; and chronic myelogenous leukemiasincluding chronic myelomonocytic leukemia, chronic granulocyticleukemia, etc. Preferred mammals include monkeys, apes, cats, dogs,cows, pigs, horses, rabbits and humans. Particularly preferred arehumans.

Pathological cell proliferative disorders are often associated withinappropriate activation of proto-oncogenes. (Gelmann, E. P. et al.,“The Etiology of Acute Leukemia: Molecular Genetics and Viral Oncology,”in Neoplastic Diseases of the Blood, Vol 1., Wiernik, P. H. et al. eds.,161-182 (1985)). Neoplasias are now believed to result from thequalitative alteration of a normal cellular gene product, or from thequantitative modification of gene expression by insertion into thechromosome of a viral sequence, by chromosomal translocation of a geneto a more actively transcribed region, or by some other mechanism.(Gelmann et al., supra) It is likely that mutated or altered expressionof specific genes is involved in the pathogenesis of some leukemias,among other tissues and cell types. (Gelmann et al., supra) Indeed, thehuman counterparts of the oncogenes involved in some animal neoplasiashave been amplified or translocated in some cases of human leukemia andcarcinoma. (Gelmann et al., supra)

For example, c-myc expression is highly amplified in the non-lymphocyticleukemia cell line HL-60. When HL-60 cells are chemically induced tostop proliferation, the level of c-myc is found to be downregulated.(International Publication Number WO 91/15580). However, it has beenshown that exposure of HL-60 cells to a DNA construct that iscomplementary to the 5′ end of c-myc or c-myb blocks translation of thecorresponding mRNAs which downregulates expression of the c-myc or c-mybproteins and causes arrest of cell proliferation and differentiation ofthe treated cells. (International Publication Number WO 91/15580;Wickstrom et al., Proc. Natl. Acad. Sci. 85:1028 (1988); Anfossi et al.,Proc. Natl. Acad. Sci. 86:3379 (1989)). However, the skilled artisanwould appreciate the present invention's usefulness is not be limited totreatment, prevention, and/or prognosis of proliferative disorders ofcells and tissues of hematopoietic origin, in light of the numerouscells and cell types of varying origins which are known to exhibitproliferative phenotypes.

In addition to the foregoing, a polynucleotide of the present inventioncan be used to control gene expression through triple helix formation orthrough antisense DNA or RNA. Antisense techniques are discussed, forexample, in Okano, J. Neurochem. 56: 560 (1991); “Oligodeoxynucleotidesas Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla.(1988). Triple helix formation is discussed in, for instance Lee et al.,Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241: 456(1988); and Dervan et al., Science 251: 1360 (1991). Both methods relyon binding of the polynucleotide to a complementary DNA or RNA. Forthese techniques, preferred polynucleotides are usually oligonucleotides20 to 40 bases in length and complementary to either the region of thegene involved in transcription (triple helix—see Lee et al., Nucl. AcidsRes. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan etal., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J.Neurochem. 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitorsof Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helixformation optimally results in a shut-off of RNA transcription from DNA,while antisense RNA hybridization blocks translation of an mRNA moleculeinto polypeptide. The oligonucleotide described above can also bedelivered to cells such that the antisense RNA or DNA may be expressedin vivo to inhibit production of polypeptide of the present inventionantigens. Both techniques are effective in model systems, and theinformation disclosed herein can be used to design antisense or triplehelix polynucleotides in an effort to treat disease, and in particular,for the treatment of proliferative diseases and/or conditions.Non-limiting antisense and triple helix methods encompassed by thepresent invention are more thoroughly described elsewhere herein (see,e.g., the section labeled “Antisense and Ribozyme (Antagonists)”).

Polynucleotides of the present invention are also useful in genetherapy. One goal of gene therapy is to insert a normal gene into anorganism having a defective gene, in an effort to correct the geneticdefect. The polynucleotides disclosed in the present invention offer ameans of targeting such genetic defects in a highly accurate manner.Another goal is to insert a new gene that was not present in the hostgenome, thereby producing a new trait in the host cell. Additionalnon-limiting examples of gene therapy methods encompassed by the presentinvention are more thoroughly described elsewhere herein (see, e.g., thesections labeled “Gene Therapy Methods”, and Examples 16, 17 and 18).

The polynucleotides are also useful for identifying indivisuals fromminute biological samples. The United States military, for example, isconsidering the use of restriction fragment length polymorphism (RFLP)for identification of its personnel. In this technique, an individual'sgenomic DNA is digested with one or more restriction enzymes, and probedon a Southern blot to yield unique bands for identifying personnel. Thismethod does not suffer from the current limitations of “Dog Tags” whichcan be lost, switched, or stolen, making positive identificationdifficult. The polynucleotides of the present invention can be used asadditional DNA markers for RFLP.

The polynucleotides of the present invention can also be used as analternative to RFLP, by determining the actual base-by-base DNA sequenceof selected portions of an individual's genome. These sequences can beused to prepare PCR primers for amplifying and isolating such selectedDNA, which can then be sequenced. Using this technique, individuals canbe identified because each individual will have a unique set of DNAsequences. Once an unique ID database is established for an individual,positive identification of that individual, living or dead, can be madefrom extremely small tissue samples.

Forensic biology also benefits from using DNA-based identificationtechniques as disclosed herein. DNA sequences taken from very smallbiological samples such as tissues, e.g., hair or skin, or body fluids,e.g., blood, saliva, semen, synovial fluid, amniotic fluid, breast milk,lymph, pulmonary sputum or surfactant, urine, fecal matter, etc., can beamplified using PCR. In one prior art technique, gene sequencesamplified from polymorphic loci, such as DQa class II HLA gene, are usedin forensic biology to identify individuals. (Erlich, H., PCRTechnology, Freeman and Co. (1992)). Once these specific polymorphicloci are amplified, they are digested with one or more restrictionenzymes, yielding an identifying set of bands on a Southern blot probedwith DNA corresponding to the DQa class II HLA gene. Similarly,polynucleotides of the present invention can be used as polymorphicmarkers for forensic purposes.

There is also a need for reagents capable of identifying the source of aparticular tissue. Such need arises, for example, in forensics whenpresented with tissue of unknown origin. Appropriate reagents cancomprise, for example, DNA probes or primers prepared from the sequencesof the present invention, specific to tissues, including but not limitedto those shown in Table 1B. Panels of such reagents can identify tissueby species and/or by organ type. In a similar fashion, these reagentscan be used to screen tissue cultures for contamination. Additionalnon-limiting examples of such uses are further described herein.

The polynucleotides of the present invention are also useful ashybridization probes for differential identification of the tissue(s) orcell type(s) present in a biological sample. Similarly, polypeptides andantibodies directed to polypeptides of the present invention are usefulto provide immunological probes for differential identification of thetissue(s) (e.g., immunohistochemistry assays) or cell type(s) (e.g.,immunocytochemistry assays). In addition, for a number of disorders ofthe above tissues or cells, significantly higher or lower levels of geneexpression of the polynucleotides/polypeptides of the present inventionmay be detected in certain tissues (e.g., tissues expressingpolypeptides and/or polynucleotides of the present invention, forexample, those disclosed in column 5 of Table 1B.2, and/or cancerousand/or wounded tissues) or bodily fluids (e.g., semen, lymph, vaginalpool, serum, plasma, urine, synovial fluid or spinal fluid) taken froman individual having such a disorder, relative to a “standard” geneexpression level, i.e., the expression level in healthy tissue from anindividual not having the disorder.

Thus, the invention provides a diagnostic method of a disorder, whichinvolves: (a) assaying gene expression level in cells or body fluid ofan individual; (b) comparing the gene expression level with a standardgene expression level, whereby an increase or decrease in the assayedgene expression level compared to the standard expression level isindicative of a disorder.

In the very least, the polynucleotides of the present invention can beused as molecular weight markers on Southern gels, as diagnostic probesfor the presence of a specific mRNA in a particular cell type, as aprobe to “subtract-out” known sequences in the process of discoveringnovel polynucleotides, for selecting and making oligomers for attachmentto a “gene chip” or other support, to raise anti-DNA antibodies usingDNA immunization techniques, and as an antigen to elicit an immuneresponse.

Uses of the Polypeptides

Each of the polypeptides identified herein can be used in numerous ways.The following description should be considered exemplary and utilizesknown techniques.

Polypeptides and antibodies directed to polypeptides of the presentinvention are useful to provide immunological probes for differentialidentification of the tissue(s) (e.g., immunohistochemistry assays suchas, for example, ABC immunoperoxidase (Hsu et al., J. Histochem.Cytochem. 29:577-580 (1981)) or cell type(s) (e.g., immunocytochemistryassays).

Antibodies can be used to assay levels of polypeptides encoded bypolynucleotides of the invention in a biological sample using classicalimmunohistological methods known to those of skill in the art (e.g., seeJalkanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al.,J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methodsuseful for detecting protein gene expression include immunoassays, suchas the enzyme linked immunosorbent assay (ELISA) and theradioimmunoassay (RIA). Suitable antibody assay labels are known in theart and include enzyme labels, such as, glucose oxidase; radioisotopes,such as iodine (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S),tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In, ¹¹¹In), andtechnetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga),palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F),¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹ Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re,¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru; luminescent labels, such as luminol; andfluorescent labels, such as fluorescein and rhodamine, and biotin.

In addition to assaying levels of polypeptide of the present inventionin a biological sample, proteins can also be detected in vivo byimaging. Antibody labels or markers for in vivo imaging of proteininclude those detectable by X-radiography, NMR or ESR. ForX-radiography, suitable labels include radioisotopes such as barium orcesium, which emit detectable radiation but are not overtly harmful tothe subject. Suitable markers for NMR and ESR include those with adetectable characteristic spin, such as deuterium, which may beincorporated into the antibody by labeling of nutrients for the relevanthybridoma.

A protein-specific antibody or antibody fragment which has been labeledwith an appropriate detectable imaging moiety, such as a radioisotope(for example, ¹³¹I, ¹¹²In, ^(99m)Tc, (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon(¹⁴C), sulfur (³⁵S), tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In,¹¹¹In), and technetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium(⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe),fluorine (¹⁸F, ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹ Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y,⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru), a radio-opaque substance, or amaterial detectable by nuclear magnetic resonance, is introduced (forexample, parenterally, subcutaneously or intraperitoneally) into themammal to be examined for immune system disorder. It will be understoodin the art that the size of the subject and the imaging system used willdetermine the quantity of imaging moiety needed to produce diagnosticimages. In the case of a radioisotope moiety, for a human subject, thequantity of radioactivity injected will normally range from about 5 to20 millicuries of ^(99m)Tc. The labeled antibody or antibody fragmentwill then preferentially accumulate at the location of cells whichexpress the polypeptide encoded by a polynucleotide of the invention. Invivo tumor imaging is described in S. W. Burchiel et al.,“Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments”(Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).

In one embodiment, the invention provides a method for the specificdelivery of compositions of the invention to cells by administeringpolypeptides of the invention (e.g., polypeptides encoded bypolynucleotides of the invention and/or antibodies) that are associatedwith heterologous polypeptides or nucleic acids. In one example, theinvention provides a method for delivering a therapeutic protein intothe targeted cell. In another example, the invention provides a methodfor delivering a single stranded nucleic acid (e.g., antisense orribozymes) or double stranded nucleic acid (e.g., DNA that can integrateinto the cell's genome or replicate episomally and that can betranscribed) into the targeted cell.

In another embodiment, the invention provides a method for the specificdestruction of cells (e.g., the destruction of tumor cells) byadministering polypeptides of the invention in association with toxinsor cytotoxic prodrugs.

By “toxin” is meant one or more compounds that bind and activateendogenous cytotoxic effector systems, radioisotopes, holotoxins,modified toxins, catalytic subunits of toxins, or any molecules orenzymes not normally present in or on the surface of a cell that underdefined conditions cause the cell's death. Toxins that may be usedaccording to the methods of the invention include, but are not limitedto, radioisotopes known in the art, compounds such as, for example,antibodies (or complement fixing containing portions thereof) that bindan inherent or induced endogenous cytotoxic effector system, thymidinekinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonasexotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweedantiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includesa cytostatic or cytocidal agent, a therapeutic agent or a radioactivemetal ion, e.g., alpha-emitters such as, for example, ²¹³Bi, or otherradioisotopes such as, for example, ¹⁰³Pd, ¹³³Xe, ¹³¹I, ⁶⁸Ge, ⁵⁷Co,⁶⁵Zn, ⁸⁵Sr, ³²P, ³⁵S, ⁹⁰Y, ¹⁵³Sm, ¹⁵³Gd, ¹⁶⁹Yb, ⁵¹Cr, ⁵⁴Mn, ⁷⁵Se, ¹¹³Sn,⁹⁰Yttrium, ¹¹⁷Tin, ¹⁸⁶Rhenium, ¹⁶⁶Holmium, and ¹⁸⁸Rhenium; luminescentlabels, such as luminol; and fluorescent labels, such as fluorescein andrhodamine, and biotin. In a specific embodiment, the invention providesa method for the specific destruction of cells (e.g., the destruction oftumor cells) by administering polypeptides of the invention orantibodies of the invention in association with the radioisotope ⁹⁰Y. Inanother specific embodiment, the invention provides a method for thespecific destruction of cells (e.g., the destruction of tumor cells) byadministering polypeptides of the invention or antibodies of theinvention in association with the radioisotope ¹¹¹In. In a furtherspecific embodiment, the invention provides a method for the specificdestruction of cells (e.g., the destruction of tumor cells) byadministering polypeptides of the invention or antibodies of theinvention in association with the radioisotope ¹³¹I.

Techniques known in the art may be applied to label polypeptides of theinvention (including antibodies). Such techniques include, but are notlimited to, the use of bifunctional conjugating agents (see e.g., U.S.Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931;5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and5,808,003; the contents of each of which are hereby incorporated byreference in its entirety).

Thus, the invention provides a diagnostic method of a disorder, whichinvolves (a) assaying the expression level of a polypeptide of thepresent invention in cells or body fluid of an individual; and (b)comparing the assayed polypeptide expression level with a standardpolypeptide expression level, whereby an increase or decrease in theassayed polypeptide expression level compared to the standard expressionlevel is indicative of a disorder. With respect to cancer, the presenceof a relatively high amount of transcript in biopsied tissue from anindividual may indicate a predisposition for the development of thedisease, or may provide a means for detecting the disease prior to theappearance of actual clinical symptoms. A more definitive diagnosis ofthis type may allow health professionals to employ preventative measuresor aggressive treatment earlier thereby preventing the development orfurther progression of the cancer.

Moreover, polypeptides of the present invention can be used to treat orprevent diseases or conditions such as, for example, neural disorders,immune system disorders, muscular disorders, reproductive disorders,gastrointestinal disorders, pulmonary disorders, cardiovasculardisorders, renal disorders, proliferative disorders, and/or cancerousdiseases and conditions. For example, patients can be administered apolypeptide of the present invention in an effort to replace absent ordecreased levels of the polypeptide (e.g., insulin), to supplementabsent or decreased levels of a different polypeptide (e.g., hemoglobinS for hemoglobin B, SOD, catalase, DNA repair proteins), to inhibit theactivity of a polypeptide (e.g., an oncogene or tumor supressor), toactivate the activity of a polypeptide (e.g., by binding to a receptor),to reduce the activity of a membrane bound receptor by competing with itfor free ligand (e.g., soluble TNF receptors used in reducinginflammation), or to bring about a desired response (e.g., blood vesselgrowth inhibition, enhancement of the immune response to proliferativecells or tissues).

Similarly, antibodies directed to a polypeptide of the present inventioncan also be used to treat disease (as described supra, and elsewhereherein). For example, administration of an antibody directed to apolypeptide of the present invention can bind, and/or neutralize thepolypeptide, and/or reduce overproduction of the polypeptide. Similarly,administration of an antibody can activate the polypeptide, such as bybinding to a polypeptide bound to a membrane (receptor).

At the very least, the polypeptides of the present invention can be usedas molecular weight markers on SDS-PAGE gels or on molecular sieve gelfiltration columns using methods well known to those of skill in theart. Polypeptides can also be used to raise antibodies, which in turnare used to measure protein expression from a recombinant cell, as a wayof assessing transformation of the host cell. Moreover, the polypeptidesof the present invention can be used to test the biological activitiesdescribed herein.

Diagnostic Assays

The compounds of the present invention are useful for diagnosis,treatment, prevention and/or prognosis of various disorders in mammals,preferably humans. Such disorders include, but are not limited to, thosedescribed in the legends for Tables 1D and 1E and as indicated in the“Preferred Indications” columns in Table 1D and Table 1E; and, also asdescribed herein under the section heading “Biological Activities”.

For a number of disorders, substantially altered (increased ordecreased) levels of gene expression can be detected in tissues, cellsor bodily fluids (e.g., sera, plasma, urine, semen, synovial fluid orspinal fluid) taken from an individual having such a disorder, relativeto a “standard” gene expression level, that is, the expression level intissues or bodily fluids from an individual not having the disorder.Thus, the invention provides a diagnostic method useful during diagnosisof a disorder, which involves measuring the expression level of the geneencoding the polypeptide in tissues, cells or body fluid from anindividual and comparing the measured gene expression level with astandard gene expression level, whereby an increase or decrease in thegene expression level(s) compared to the standard is indicative of adisorder. These diagnostic assays may be performed in vivo or in vitro,such as, for example, on blood samples, biopsy tissue or autopsy tissue.

The present invention is also useful as a prognostic indicator, wherebypatients exhibiting enhanced or depressed gene expression willexperience a worse clinical outcome relative to patients expressing thegene at a level nearer the standard level.

In certain embodiments, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to diagnose and/or prognose diseasesand/or disorders associated with the tissue(s) in which the polypeptideof the invention is expressed, including one, two, three, four, five, ormore tissues disclosed in Table 1B.2, column 5 (Tissue DistributionLibrary Code).

By “assaying the expression level of the gene encoding the polypeptide”is intended qualitatively or quantitatively measuring or estimating thelevel of the polypeptide of the invention or the level of the mRNAencoding the polypeptide of the invention in a first biological sampleeither directly (e.g., by determining or estimating absolute proteinlevel or mRNA level) or relatively (e.g., by comparing to thepolypeptide level or mRNA level in a second biological sample).Preferably, the polypeptide expression level or mRNA level in the firstbiological sample is measured or estimated and compared to a standardpolypeptide level or mRNA level, the standard being taken from a secondbiological sample obtained from an individual not having the disorder orbeing determined by averaging levels from a population of individualsnot having the disorder. As will be appreciated in the art, once astandard polypeptide level or mRNA level is known, it can be usedrepeatedly as a standard for comparison.

By “biological sample” is intended any biological sample obtained froman individual, cell line, tissue culture, or other source containingpolypeptides of the invention (including portions thereof) or mRNA. Asindicated, biological samples include body fluids (such as sera, plasma,urine, synovial fluid and spinal fluid) and tissue sources found toexpress the full length or fragments thereof of a polypeptide or mRNA.Methods for obtaining tissue biopsies and body fluids from mammals arewell known in the art. Where the biological sample is to include mRNA, atissue biopsy is the preferred source.

Total cellular RNA can be isolated from a biological sample using anysuitable technique such as the single-stepguanidinium-thiocyanate-phenol-chloroform method described inChomczynski and Sacchi, Anal. Biochem. 162:156-159 (1987). Levels ofmRNA encoding the polypeptides of the invention are then assayed usingany appropriate method. These include Northern blot analysis, S1nuclease mapping, the polymerase chain reaction (PCR), reversetranscription in combination with the polymerase chain reaction(RT-PCR), and reverse transcription in combination with the ligase chainreaction (RT-LCR).

The present invention also relates to diagnostic assays such asquantitative and diagnostic assays for detecting levels of polypeptidesof the invention, in a biological sample (e.g., cells and tissues),including determination of normal and abnormal levels of polypeptides.Thus, for instance, a diagnostic assay in accordance with the inventionfor detecting over-expression of polypeptides of the invention comparedto normal control tissue samples may be used to detect the presence oftumors. Assay techniques that can be used to determine levels of apolypeptide, such as a polypeptide of the present invention in a samplederived from a host are well-known to those of skill in the art. Suchassay methods include radioimmunoassays, competitive-binding assays,Western Blot analysis and ELISA assays. Assaying polypeptide levels in abiological sample can occur using any art-known method.

Assaying polypeptide levels in a biological sample can occur usingantibody-based techniques. For example, polypeptide expression intissues can be studied with classical immunohistological methods(Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., etal., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methodsuseful for detecting polypeptide gene expression include immunoassays,such as the enzyme linked immunosorbent assay (ELISA) and theradioimmunoassay (RIA). Suitable antibody assay labels are known in theart and include enzyme labels, such as, glucose oxidase, andradioisotopes, such as iodine (¹²⁵I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S),tritium (³H), indium (¹¹²In), and technetium (^(99m)Tc), and fluorescentlabels, such as fluorescein and rhodamine, and biotin.

The tissue or cell type to be analyzed will generally include thosewhich are known, or suspected, to express the gene of inteest (such as,for example, cancer). The protein isolation methods employed herein may,for example, be such as those described in Harlow and Lane (Harlow, E.and Lane, D., 1988, “Antibodies: A Laboratory Manual”, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y.), which isincorporated herein by reference in its entirety. The isolated cells canbe derived from cell culture or from a patient. The analysis of cellstaken from culture may be a necessary step in the assessment of cellsthat could be used as part of a cell-based gene therapy technique or,alternatively, to test the effect of compounds on the expression of thegene.

For example, antibodies, or fragments of antibodies, such as thosedescribed herein, may be used to quantitatively or qualitatively detectthe presence of gene products or conserved variants or peptide fragmentsthereof. This can be accomplished, for example, by immunofluorescencetechniques employing a fluorescently labeled antibody coupled with lightmicroscopic, flow cytometric, or fluorimetric detection.

In a preferred embodiment, antibodies, or fragments of antibodiesdirected to any one or all of the predicted epitope domains of thepolypeptides of the invention (shown in column 7 of Table 1B.1) may beused to quantitatively or qualitatively detect the presence of geneproducts or conserved variants or peptide fragments thereof. This can beaccomplished, for example, by immunofluorescence techniques employing afluorescently labeled antibody coupled with light microscopic, flowcytometric, or fluorimetric detection.

In an additional preferred embodiment, antibodies, or fragments ofantibodies directed to a conformational epitope of a polypeptide of theinvention may be used to quantitatively or qualitatively detect thepresence of gene products or conserved variants or peptide fragmentsthereof. This can be accomplished, for example, by immunofluorescencetechniques employing a fluorescently labeled antibody coupled with lightmicroscopic, flow cytometric, or fluorimetric detection.

The antibodies (or fragments thereof), and/or polypeptides of thepresent invention may, additionally, be employed histologically, as inimmunofluorescence, immunoelectron microscopy or non-immunologicalassays, for in situ detection of gene products or conserved variants orpeptide fragments thereof. In situ detection may be accomplished byremoving a histological specimen from a patient, and applying thereto alabeled antibody or polypeptide of the present invention. The antibody(or fragment thereof) or polypeptide is preferably applied by overlayingthe labeled antibody (or fragment) onto a biological sample. Through theuse of such a procedure, it is possible to determine not only thepresence of the gene product, or conserved variants or peptidefragments, or polypeptide binding, but also its distribution in theexamined tissue. Using the present invention, those of ordinary skillwill readily perceive that any of a wide variety of histological methods(such as staining procedures) can be modified in order to achieve suchin situ detection.

Immunoassays and non-immunoassays for gene products or conservedvariants or peptide fragments thereof will typically comprise incubatinga sample, such as a biological fluid, a tissue extract, freshlyharvested cells, or lysates of cells which have been incubated in cellculture, in the presence of a detectably labeled antibody capable ofbinding gene products or conserved variants or peptide fragmentsthereof, and detecting the bound antibody by any of a number oftechniques well-known in the art.

The biological sample may be brought in contact with and immobilizedonto a solid phase support or carrier such as nitrocellulose, or othersolid support which is capable of immobilizing cells, cell particles orsoluble proteins. The support may then be washed with suitable buffersfollowed by treatment with the detectably labeled antibody or detectablepolypeptide of the invention. The solid phase support may then be washedwith the buffer a second time to remove unbound antibody or polypeptide.Optionally the antibody is subsequently labeled. The amount of boundlabel on solid support may then be detected by conventional means.

By “solid phase support or carrier” is intended any support capable ofbinding an antigen or an antibody. Well-known supports or carriersinclude glass, polystyrene, polypropylene, polyethylene, dextran, nylon,amylases, natural and modified celluloses, polyacrylamides, gabbros, andmagnetite. The nature of the carrier can be either soluble to someextent or insoluble for the purposes of the present invention. Thesupport material may have virtually any possible structuralconfiguration so long as the coupled molecule is capable of binding toan antigen or antibody. Thus, the support configuration may bespherical, as in a bead, or cylindrical, as in the inside surface of atest tube, or the external surface of a rod. Alternatively, the surfacemay be flat such as a sheet, test strip, etc. Preferred supports includepolystyrene beads. Those skilled in the art will know many othersuitable carriers for binding antibody or antigen, or will be able toascertain the same by use of routine experimentation.

The binding activity of a given lot of antibody or antigen polypeptidemay be determined according to well known methods. Those skilled in theart will be able to determine operative and optimal assay conditions foreach determination by employing routine experimentation.

In addition to assaying polypeptide levels or polynucleotide levels in abiological sample obtained from an individual, polypeptide orpolynucleotide can also be detected in vivo by imaging. For example, inone embodiment of the invention, polypeptides and/or antibodies of theinvention are used to image diseased cells, such as neoplasms. Inanother embodiment, polynucleotides of the invention (e.g.,polynucleotides complementary to all or a portion of an mRNA) and/orantibodies (e.g., antibodies directed to any one or a combination of theepitopes of a polypeptide of the invention, antibodies directed to aconformational epitope of a polypeptide of the invention, or antibodiesdirected to the full length polypeptide expressed on the cell surface ofa mammalian cell) are used to image diseased or neoplastic cells.

Antibody labels or markers for in vivo imaging of polypeptides of theinvention include those detectable by X-radiography, NMR, MRI, CAT-scansor ESR. For X-radiography, suitable labels include radioisotopes such asbarium or cesium, which emit detectable radiation but are not overtlyharmful to the subject. Suitable markers for NMR and ESR include thosewith a detectable characteristic spin, such as deuterium, which may beincorporated into the antibody by labeling of nutrients for the relevanthybridoma. Where in vivo imaging is used to detect enhanced levels ofpolypeptides for diagnosis in humans, it may be preferable to use humanantibodies or “humanized” chimeric monoclonal antibodies. Suchantibodies can be produced using techniques described herein orotherwise known in the art. For example methods for producing chimericantibodies are known in the art. See, for review, Morrison, Science229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al.,U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al.,EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671;Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature314:268 (1985).

Additionally, any polypeptides of the invention whose presence can bedetected, can be administered. For example, polypeptides of theinvention labeled with a radio-opaque or other appropriate compound canbe administered and visualized in vivo, as discussed, above for labeledantibodies. Further, such polypeptides can be utilized for in vitrodiagnostic procedures.

A polypeptide-specific antibody or antibody fragment which has beenlabeled with an appropriate detectable imaging moiety, such as aradioisotope (for example, ¹³¹I, ¹¹²In, ^(99m)Tc), a radio-opaquesubstance, or a material detectable by nuclear magnetic resonance, isintroduced (for example, parenterally, subcutaneously orintraperitoneally) into the mammal to be examined for a disorder. Itwill be understood in the art that the size of the subject and theimaging system used will determine the quantity of imaging moiety neededto produce diagnostic images. In the case of a radioisotope moiety, fora human subject, the quantity of radioactivity injected will normallyrange from about 5 to 20 millicuries of ^(99m)Tc. The labeled antibodyor antibody fragment will then preferentially accumulate at the locationof cells which contain the antigenic protein. In vivo tumor imaging isdescribed in S. W. Burchiel et al., “Immunopharmacokinetics ofRadiolabeled Antibodies and Their Fragments” (Chapter 13 in TumorImaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A.Rhodes, eds., Masson Publishing Inc. (1982)).

With respect to antibodies, one of the ways in which an antibody of thepresent invention can be detectably labeled is by linking the same to areporter enzyme and using the linked product in an enzyme immunoassay(EIA) (Voller, A., “The Enzyme Linked Immunosorbent Assay (ELISA)”,1978, Diagnostic Horizons 2:1-7, Microbiological Associates QuarterlyPublication, Walkersville, Md.); Voller et al., J. Clin. Pathol.31:507-520 (1978); Butler, J. E., Meth. Enzymol. 73:482-523 (1981);Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton,Fla.,; Ishikawa, E. et al., (eds.), 1981, Enzyme Immunoassay, KgakuShoin, Tokyo). The reporter enzyme which is bound to the antibody willreact with an appropriate substrate, preferably a chromogenic substrate,in such a manner as to produce a chemical moiety which can be detected,for example, by spectrophotometric, fluorimetric or by visual means.Reporter enzymes which can be used to detectably label the antibodyinclude, but are not limited to, malate dehydrogenase, staphylococcalnuclease, delta-5-steroid isomerase, yeast alcohol dehydrogenase,alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase,horseradish peroxidase, alkaline phosphatase, asparaginase, glucoseoxidase, beta-galactosidase, ribonuclease, urease, catalase,glucose-6-phosphate dehydrogenase, glucoamylase andacetylcholinesterase. Additionally, the detection can be accomplished bycolorimetric methods which employ a chromogenic substrate for thereporter enzyme. Detection may also be accomplished by visual comparisonof the extent of enzymatic reaction of a substrate in comparison withsimilarly prepared standards.

Detection may also be accomplished using any of a variety of otherimmunoassays. For example, by radioactively labeling the antibodies orantibody fragments, it is possible to detect polypeptides through theuse of a radioimmunoassay (RIA) (see, for example, Weintraub, B.,Principles of Radioimmunoassays, Seventh Training Course on RadioligandAssay Techniques, The Endocrine Society, March, 1986, which isincorporated by reference herein). The radioactive isotope can bedetected by means including, but not limited to, a gamma counter, ascintillation counter, or autoradiography.

It is also possible to label the antibody with a fluorescent compound.When the fluorescently labeled antibody is exposed to light of theproper wave length, its presence can then be detected due tofluorescence. Among the most commonly used fluorescent labelingcompounds are fluorescein isothiocyanate, rhodamine, phycoerythrin,phycocyanin, allophycocyanin, ophthaldehyde and fluorescamine.

The antibody can also be detectably labeled using fluorescence emittingmetals such as ¹⁵²Eu, or others of the lanthanide series. These metalscan be attached to the antibody using such metal chelating groups asdiethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraaceticacid (EDTA).

The antibody also can be detectably labeled by coupling it to achemiluminescent compound. The presence of the chemiluminescent-taggedantibody is then determined by detecting the presence of luminescencethat arises during the course of a chemical reaction. Examples ofparticularly useful chemiluminescent labeling compounds are luminol,isoluminol, theromatic acridinium ester, imidazole, acridinium salt andoxalate ester.

Likewise, a bioluminescent compound may be used to label the antibody ofthe present invention. Bioluminescence is a type of chemiluminescencefound in biological systems in, which a catalytic protein increases theefficiency of the chemiluminescent reaction. The presence of abioluminescent protein is determined by detecting the presence ofluminescence. Important bioluminescent compounds for purposes oflabeling are luciferin, luciferase and aequorin.

Methods for Detecting Diseases

In general, a disease may be detected in a patient based on the presenceof one or more proteins of the invention and/or polynucleotides encodingsuch proteins in a biological sample (for example, blood, sera, urine,and/or tumor biopsies) obtained from the patient. In other words, suchproteins may be used as markers to indicate the presence or absence of adisease or disorder, including cancer and/or as described elsewhereherein. In addition, such proteins may be useful for the detection ofother diseases and cancers. The binding agents provided herein generallypermit detection of the level of antigen that binds to the agent in thebiological sample. Polynucleotide primers and probes may be used todetect the level of mRNA encoding polypeptides of the invention, whichis also indicative of the presence or absence of a disease or disorder,including cancer. In general, polypeptides of the invention should bepresent at a level that is at least three fold higher in diseased tissuethan in normal tissue.

There are a variety of assay formats known to those of ordinary skill inthe art for using a binding agent to detect polypeptide markers in asample. See, e.g., Harlow and Lane, supra. In general, the presence orabsence of a disease in a patient may be determined by (a) contacting abiological sample obtained from a patient with a binding agent; (b)detecting in the sample a level of polypeptide that binds to the bindingagent; and (c) comparing the level of polypeptide with a predeterminedcut-off value.

In a preferred embodiment, the assay involves the use of a bindingagent(s) immobilized on a solid support to bind to and remove thepolypeptide of the invention from the remainder of the sample. The boundpolypeptide may then be detected using a detection reagent that containsa reporter group and specifically binds to the binding agent/polypeptidecomplex. Such detection reagents may comprise, for example, a bindingagent that specifically binds to the polypeptide or an antibody or otheragent that specifically binds to the binding agent, such as ananti-immunoglobulin, protein G, protein A or a lectin. Alternatively, acompetitive assay may be utilized, in which a polypeptide is labeledwith a reporter group and allowed to bind to the immobilized bindingagent after incubation of the binding agent with the sample. The extentto which components of the sample inhibit the binding of the labeledpolypeptide to the binding agent is indicative of the reactivity of thesample with the immobilized binding agent. Suitable polypeptides for usewithin such assays include polypeptides of the invention and portionsthereof, or antibodies, to which the binding agent binds, as describedabove.

The solid support may be any material known to those of skill in the artto which polypeptides of the invention may be attached. For example, thesolid support may be a test well in a microtiter plate or anitrocellulose or other suitable membrane. Alternatively, the supportmay be a bead or disc, such as glass fiberglass, latex or a plasticmaterial such as polystyrene or polyvinylchloride. The support may alsobe a magnetic particle or a fiber optic sensor, such as those disclosed,for example, in U.S. Pat. No. 5,359,681. The binding agent may beimmobilized on the solid support using a variety of techniques known tothose of skill in the art, which are amply described in the patent andscientific literature. In the context of the present invention, the term“immobilization” refers to both noncovalent association, such asadsorption, and covalent attachment (which may be a direct linkagebetween the agent and functional groups on the support or may be alinkage by way of a cross-linking agent). Immobilization by adsorptionto a well in a microtiter plate or to a membrane is preferred. In suchcases, adsorption may be achieved by contacting the binding agent, in asuitable buffer, with the solid support for the suitable amount of time.The contact time varies with temperature, but is typically between about1 hour and about 1 day. In general, contacting a well of plasticmicrotiter plate (such as polystyrene or polyvinylchloride) with anamount of binding agent ranging from about 10 ng to about 10 ug, andpreferably about 100 ng to about 1 ug, is sufficient to immobilize anadequate amount of binding agent.

Covalent attachment of binding agent to a solid support may generally beachieved by first reacting the support with a bifunctional reagent thatwill react with both the support and a functional group, such as ahydroxyl or amino group, on the binding agent. For example, the bindingagent may be covalently attached to supports having an appropriatepolymer coating using benzoquinone or by condensation of an aldehydegroup on the support with an amine and an active hydrogen on the bindingpartner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991,at A12-A13).

Gene Therapy Methods

Also encompassed by the invention are gene therapy methods for treatingor preventing disorders, diseases and conditions. The gene therapymethods relate to the introduction of nucleic acid (DNA, RNA andantisense DNA or RNA) sequences into an animal to achieve expression ofthe polypeptide of the present invention. This method requires apolynucleotide which codes for a polypeptide of the present inventionoperatively linked to a promoter and any other genetic elementsnecessary for the expression of the polypeptide by the target tissue.Such gene therapy and delivery techniques are known in the art, see, forexample, WO90/11092, which is herein incorporated by reference.

Thus, for example, cells from a patient may be engineered with apolynucleotide (DNA or RNA) comprising a promoter operably linked to apolynucleotide of the present invention ex vivo, with the engineeredcells then being provided to a patient to be treated with thepolypeptide of the present invention. Such methods are well-known in theart. For example, see Belldegrun, A., et al., J. Natl. Cancer Inst. 85:207-216 (1993); Ferrantini, M. et al., Cancer Research 53: 1107-1112(1993); Ferrantini, M. et al., J. Immunology 153: 4604-4615 (1994);Kaido, T., et al., Int. J. Cancer 60: 221-229 (1995); Ogura, H., et al.,Cancer Research 50: 5102-5106 (1990); Santodonato, L., et al., HumanGene Therapy 7:1-10 (1996); Santodonato, L., et al., Gene Therapy4:1246-1255 (1997); and Zhang, J.-F. et al., Cancer Gene Therapy 3:31-38 (1996)), which are herein incorporated by reference. In oneembodiment, the cells which are engineered are arterial cells. Thearterial cells may be reintroduced into the patient through directinjection to the artery, the tissues surrounding the artery, or throughcatheter injection.

As discussed in more detail below, the polynucleotide constructs can bedelivered by any method that delivers injectable materials to the cellsof an animal, such as, injection into the interstitial space of tissues(heart, muscle, skin, lung, liver, and the like). The polynucleotideconstructs may be delivered in a pharmaceutically acceptable liquid oraqueous carrier.

In one embodiment, the polynucleotide of the present invention isdelivered as a naked polynucleotide. The term “naked” polynucleotide,DNA or RNA refers to sequences that are free from any delivery vehiclethat acts to assist, promote or facilitate entry into the cell,including viral sequences, viral particles, liposome formulations,lipofectin or precipitating agents and the like. However, thepolynucleotide of the present invention can also be delivered inliposome formulations and lipofectin formulations and the like can beprepared by methods well known to those skilled in the art. Such methodsare described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and5,580,859, which are herein incorporated by reference.

The polynucleotide vector constructs used in the gene therapy method arepreferably constructs that will not integrate into the host genome norwill they contain sequences that allow for replication. Appropriatevectors include pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available fromStratagene; pSVK3, pBPV, pMSG and pSVL available from Pharmacia; andpEF1/V5, pcDNA3.1, and pRc/CMV2 available from Invitrogen. Othersuitable vectors will be readily apparent to the skilled artisan.

Any strong promoter known to those skilled in the art can be used fordriving the expression of the polynucleotide sequence. Suitablepromoters include adenoviral promoters, such as the adenoviral majorlate promoter; or heterologous promoters, such as the cytomegalovirus(CMV) promoter; the respiratory syncytial virus (RSV) promoter;inducible promoters, such as the MMT promoter, the metallothioneinpromoter; heat shock promoters; the albumin promoter; the ApoAIpromoter; human globin promoters; viral thymidine kinase promoters, suchas the Herpes Simplex thymidine kinase promoter; retroviral LTRs; theb-actin promoter; and human growth hormone promoters. The promoter alsomay be the native promoter for the polynucleotide of the presentinvention.

Unlike other gene therapy techniques, one major advantage of introducingnaked nucleic acid sequences into target cells is the transitory natureof the polynucleotide synthesis in the cells. Studies have shown thatnon-replicating DNA sequences can be introduced into cells to provideproduction of the desired polypeptide for periods of up to six months.

The polynucleotide construct can be delivered to the interstitial spaceof tissues within the an animal, including of muscle, skin, brain, lung,liver, spleen, bone marrow, thymus, heart, lymph, blood, bone,cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis,ovary, uterus, rectum, nervous system, eye, gland, and connectivetissue. Interstitial space of the tissues comprises the intercellular,fluid, mucopolysaccharide matrix among the reticular fibers of organtissues, elastic fibers in the walls of vessels or chambers, collagenfibers of fibrous tissues, or that same matrix within connective tissueensheathing muscle cells or in the lacunae of bone. It is similarly thespace occupied by the plasma of the circulation and the lymph fluid ofthe lymphatic channels. Delivery to the interstitial space of muscletissue is preferred for the reasons discussed below. They may beconveniently delivered by injection into the tissues comprising thesecells. They are preferably delivered to and expressed in persistent,non-dividing cells which are differentiated, although delivery andexpression may be achieved in non-differentiated or less completelydifferentiated cells, such as, for example, stem cells of blood or skinfibroblasts. In vivo muscle cells are particularly competent in theirability to take up and express polynucleotides.

For the naked nucleic acid sequence injection, an effective dosageamount of DNA or RNA will be in the range of from about 0.05 mg/kg bodyweight to about 50 mg/kg body weight. Preferably the dosage will be fromabout 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill willappreciate, this dosage will vary according to the tissue site ofinjection. The appropriate and effective dosage of nucleic acid sequencecan readily be determined by those of ordinary skill in the art and maydepend on the condition being treated and the route of administration.

The preferred route of administration is by the parenteral route ofinjection into the interstitial space of tissues. However, otherparenteral routes may also be used, such as, inhalation of an aerosolformulation particularly for delivery to lungs or bronchial tissues,throat or mucous membranes of the nose. In addition, naked DNAconstructs can be delivered to arteries during angioplasty by thecatheter used in the procedure.

The naked polynucleotides are delivered by any method known in the art,including, but not limited to, direct needle injection at the deliverysite, intravenous injection, topical administration, catheter infusion,and so-called “gene guns”. These delivery methods are known in the art.

The constructs may also be delivered with delivery vehicles such asviral sequences, viral particles, liposome formulations, lipofectin,precipitating agents, etc. Such methods of delivery are known in theart.

In certain embodiments, the polynucleotide constructs are complexed in aliposome preparation. Liposomal preparations for use in the instantinvention include cationic (positively charged), anionic (negativelycharged) and neutral preparations. However, cationic liposomes areparticularly preferred because a tight charge complex can be formedbetween the cationic liposome and the polyanionic nucleic acid. Cationicliposomes have been shown to mediate intracellular delivery of plasmidDNA (Felgner et al., Proc. Natl. Acad. Sci. USA (1987) 84:7413-7416,which is herein incorporated by reference); mRNA (Malone et al., Proc.Natl. Acad. Sci. USA (1989) 86:6077-6081, which is herein incorporatedby reference); and purified transcription factors (Debs et al., J. Biol.Chem. (1990) 265:10189-10192, which is herein incorporated byreference), in functional form.

Cationic liposomes are readily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes areparticularly useful and are available under the trademark Lipofectin,from GIBCO BRL, Grand Island, N.Y. (See, also, Felgner et al., Proc.Natl. Acad. Sci. USA (1987) 84:7413-7416, which is herein incorporatedby reference). Other commercially available liposomes includetransfectace (DDAB/DOPE) and DOTAP/DOPE (Boehringer).

Other cationic liposomes can be prepared from readily availablematerials using techniques well known in the art. See, e.g. PCTPublication No. WO 90/11092 (which is herein incorporated by reference)for a description of the synthesis of DOTAP(1,2-bis(oleoyloxy)-3-(trimethylammonio)propane) liposomes. Preparationof DOTMA liposomes is explained in the literature, see, e.g., P. Felgneret al., Proc. Natl. Acad. Sci. USA 84:7413-7417, which is hereinincorporated by reference. Similar methods can be used to prepareliposomes from other cationic lipid materials.

Similarly, anionic and neutral liposomes are readily available, such asfrom Avanti Polar Lipids (Birmingham, Ala.), or can be easily preparedusing readily available materials. Such materials include phosphatidyl,choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidyl glycerol (DOPG),dioleoylphoshatidyl ethanolamine (DOPE), among others. These materialscan also be mixed with the DOTMA and DOTAP starting materials inappropriate ratios. Methods for making liposomes using these materialsare well known in the art.

For example, commercially dioleoylphosphatidyl choline (DOPC),dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidylethanolamine (DOPE) can be used in various combinations to makeconventional liposomes, with or without the addition of cholesterol.Thus, for example, DOPG/DOPC vesicles can be prepared by drying 50 mgeach of DOPG and DOPC under a stream of nitrogen gas into a sonicationvial. The sample is placed under a vacuum pump overnight and is hydratedthe following day with deionized water. The sample is then sonicated for2 hours in a capped vial, using a Heat Systems model 350 sonicatorequipped with an inverted cup (bath type) probe at the maximum settingwhile the bath is circulated at 15EC. Alternatively, negatively chargedvesicles can be prepared without sonication to produce multilamellarvesicles or by extrusion through nucleopore membranes to produceunilamellar vesicles of discrete size. Other methods are known andavailable to those of skill in the art.

The liposomes can comprise multilamellar vesicles (MLVs), smallunilamellar vesicles (SUVs), or large unilamellar vesicles (LUVs), withSUVs being preferred. The various liposome-nucleic acid complexes areprepared using methods well known in the art. See, e.g., Straubinger etal., Methods of Immunology (1983), 101:512-527, which is hereinincorporated by reference. For example, MLVs containing nucleic acid canbe prepared by depositing a thin film of phospholipid on the walls of aglass tube and subsequently hydrating with a solution of the material tobe encapsulated. SUVs are prepared by extended sonication of MLVs toproduce a homogeneous population of unilamellar liposomes. The materialto be entrapped is added to a suspension of preformed MLVs and thensonicated. When using liposomes containing cationic lipids, the driedlipid film is resuspended in an appropriate solution such as sterilewater or an isotonic buffer solution such as 10 mM Tris/NaCl, sonicated,and then the preformed liposomes are mixed directly with the DNA. Theliposome and DNA form a very stable complex due to binding of thepositively charged liposomes to the cationic DNA. SUVs find use withsmall nucleic acid fragments. LUVs are prepared by a number of methods,well known in the art. Commonly used methods include Ca²⁺-EDTA chelation(Papahadjopoulos et al., Biochim. Biophys. Acta (1975) 394:483; Wilsonet al., Cell 17:77 (1979)); ether injection (Deamer, D. and Bangham, A.,Biochim. Biophys. Acta 443:629 (1976); Ostro et al., Biochem. Biophys.Res. Commun. 76:836 (1977); Fraley et al., Proc. Natl. Acad. Sci. USA76:3348 (1979)); detergent dialysis (Enoch, H. and Strittmatter, P.,Proc. Natl. Acad. Sci. USA 76:145 (1979)); and reverse-phase evaporation(REV) (Fraley et al., J. Biol. Chem. 255:10431 (1980); Szoka, F. andPapahadjopoulos, D., Proc. Natl. Acad. Sci. USA 75:145 (1978);Schaefer-Ridder et al., Science 215:166 (1982)), which are hereinincorporated by reference.

Generally, the ratio of DNA to liposomes will be from about 10:1 toabout 1:10. Preferably, the ration will be from about 5:1 to about 1:5.More preferably, the ration will be about 3:1 to about 1:3. Still morepreferably, the ratio will be about 1:1.

U.S. Pat. No. 5,676,954 (which is herein incorporated by reference)reports on the injection of genetic material, complexed with cationicliposomes carriers, into mice. U.S. Pat. Nos. 4,897,355, 4,946,787,5,049,386, 5,459,127, 5,589,466, 5,693,622, 5,580,859, 5,703,055, andinternational publication no. WO 94/9469 (which are herein incorporatedby reference) provide cationic lipids for use in transfecting DNA intocells and mammals. U.S. Pat. Nos. 5,589,466, 5,693,622, 5,580,859,5,703,055, and international publication no. WO 94/9469 provide methodsfor delivering DNA-cationic lipid complexes to mammals.

In certain embodiments, cells are engineered, ex vivo or in vivo, usinga retroviral particle containing RNA which comprises a sequence encodinga polypeptide of the present invention. Retroviruses from which theretroviral plasmid vectors may be derived include, but are not limitedto, Moloney Murine Leukemia Virus, spleen necrosis virus, Rous sarcomaVirus, Harvey Sarcoma Virus, avian leukosis virus, gibbon ape leukemiavirus, human immunodeficiency virus, Myeloproliferative Sarcoma Virus,and mammary tumor virus.

The retroviral plasmid vector is employed to transduce packaging celllines to form producer cell lines. Examples of packaging cells which maybe transfected include, but are not limited to, the PE501, PA317, R-2,R-AM, PA12, T19-14X, VT-19-17-H2, RCRE, RCRIP, GP+E-86, GP+envAm12, andDAN cell lines as described in Miller, Human Gene Therapy 1:5-14 (1990),which is incorporated herein by reference in its entirety. The vectormay transduce the packaging cells through any means known in the art.Such means include, but are not limited to, electroporation, the use ofliposomes, and CaPO₄ precipitation. In one alternative, the retroviralplasmid vector may be encapsulated into a liposome, or coupled to alipid, and then administered to a host.

The producer cell line generates infectious retroviral vector particleswhich include polynucleotide encoding a polypeptide of the presentinvention. Such retroviral vector particles then may be employed, totransduce eukaryotic cells, either in vitro or in vivo. The transducedeukaryotic cells will express a polypeptide of the present invention.

In certain other embodiments, cells are engineered, ex vivo or in vivo,with polynucleotide contained in an adenovirus vector. Adenovirus can bemanipulated such that it encodes and expresses a polypeptide of thepresent invention, and at the same time is inactivated in terms of itsability to replicate in a normal lytic viral life cycle. Adenovirusexpression is achieved without integration of the viral DNA into thehost cell chromosome, thereby alleviating concerns about insertionalmutagenesis. Furthermore, adenoviruses have been used as live entericvaccines for many years with an excellent safety profile (Schwartz etal. Am. Rev. Respir. Dis. 109:233-238 (1974)). Finally, adenovirusmediated gene transfer has been demonstrated in a number of instancesincluding transfer of alpha-1-antitrypsin and CFTR to the lungs ofcotton rats (Rosenfeld, M. A. et al. (1991) Science 252:431-434;Rosenfeld et al., (1992) Cell 68:143-155). Furthermore, extensivestudies to attempt to establish adenovirus as a causative agent in humancancer were uniformly negative (Green, M. et al. (1979) Proc. Natl.Acad. Sci. USA 76:6606).

Suitable adenoviral vectors useful in the present invention aredescribed, for example, in Kozarsky and Wilson, Curr. Opin. Genet.Devel. 3:499-503 (1993); Rosenfeld et al., Cell 68:143-155 (1992);Engelhardt et al., Human Genet. Ther. 4:759-769 (1993); Yang et al.,Nature Genet. 7:362-369 (1994); Wilson et al., Nature 365:691-692(1993); and U.S. Pat. No. 5,652,224, which are herein incorporated byreference. For example, the adenovirus vector Ad2 is useful and can begrown in human 293 cells. These cells contain the E1 region ofadenovirus and constitutively express E1a and E1b, which complement thedefective adenoviruses by providing the products of the genes deletedfrom the vector. In addition to Ad2, other varieties of adenovirus(e.g., Ad3, Ad5, and Ad7) are also useful in the present invention.

Preferably, the adenoviruses used in the present invention arereplication deficient. Replication deficient adenoviruses require theaid of a helper virus and/or packaging cell line to form infectiousparticles. The resulting virus is capable of infecting cells and canexpress a polynucleotide of interest which is operably linked to apromoter, but cannot replicate in most cells. Replication deficientadenoviruses may be deleted in one or more of all or a portion of thefollowing genes: E1a, E1b, E3, E4, E2a, or L1 through L5.

In certain other embodiments, the cells are engineered, ex vivo or invivo, using an adeno-associated virus (AAV). AAVs are naturallyoccurring defective viruses that require helper viruses to produceinfectious particles (Muzyczka, N., Curr. Topics in Microbiol. Immunol.158:97 (1992)). It is also one of the few viruses that may integrate itsDNA into non-dividing cells. Vectors containing as little as 300 basepairs of AAV can be packaged and can integrate, but space for exogenousDNA is limited to about 4.5 kb. Methods for producing and using suchAAVs are known in the art. See, for example, U.S. Pat. Nos. 5,139,941,5,173,414, 5,354,678, 5,436,146, 5,474,935, 5,478,745, and 5,589,377.

For example, an appropriate AAV vector for use in the present inventionwill include all the sequences necessary for DNA replication,encapsidation, and host-cell integration. The polynucleotide constructis inserted into the AAV vector using standard cloning methods, such asthose found in Sambrook et al., Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Press (1989). The recombinant AAV vector is thentransfected into packaging cells which are infected with a helper virus,using any standard technique, including lipofection, electroporation,calcium phosphate precipitation, etc. Appropriate helper viruses includeadenoviruses, cytomegaloviruses, vaccinia viruses, or herpes viruses.Once the packaging cells are transfected and infected, they will produceinfectious AAV viral particles which contain the polynucleotideconstruct. These viral particles are then used to transduce eukaryoticcells, either ex vivo or in vivo. The transduced cells will contain thepolynucleotide construct integrated into its genome, and will express apolypeptide of the invention.

Another method of gene therapy involves operably associatingheterologous control regions and endogenous polynucleotide sequences(e.g. encoding a polypeptide of the present invention) via homologousrecombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997;International Publication No. WO 96/29411, published Sep. 26, 1996;International Publication No. WO 94/12650, published Aug. 4, 1994;Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); andZijlstra et al., Nature 342:435-438 (1989), which are hereinencorporated by reference. This method involves the activation of a genewhich is present in the target cells, but which is not normallyexpressed in the cells, or is expressed at a lower level than desired.

Polynucleotide constructs are made, using standard techniques known inthe art, which contain the promoter with targeting sequences flankingthe promoter. Suitable promoters are described herein. The targetingsequence is sufficiently complementary to an endogenous sequence topermit homologous recombination of the promoter-targeting sequence withthe endogenous sequence. The targeting sequence will be sufficientlynear the 5′ end of the desired endogenous polynucleotide sequence so thepromoter will be operably linked to the endogenous sequence uponhomologous recombination.

The promoter and the targeting sequences can be amplified using PCR.Preferably, the amplified promoter contains distinct restriction enzymesites on the 5′ and 3′ ends. Preferably, the 3′ end of the firsttargeting sequence contains the same restriction enzyme site as the 5′end of the amplified promoter and the 5′ end of the second targetingsequence contains the same restriction site as the 3′ end of theamplified promoter. The amplified promoter and targeting sequences aredigested and ligated together.

The promoter-targeting sequence construct is delivered to the cells,either as naked polynucleotide, or in conjunction withtransfection-facilitating agents, such as liposomes, viral sequences,viral particles, whole viruses, lipofection, precipitating agents, etc.,described in more detail above. The P promoter-targeting sequence can bedelivered by any method, included direct needle injection, intravenousinjection, topical administration, catheter infusion, particleaccelerators, etc. The methods are described in more detail below.

The promoter-targeting sequence construct is taken up by cells.Homologous recombination between the construct and the endogenoussequence takes place, such that an endogenous sequence is placed underthe control of the promoter. The promoter then drives the expression ofthe endogenous sequence.

The polynucleotide encoding a polypeptide of the present invention maycontain a secretory signal sequence that facilitates secretion of theprotein. Typically, the signal sequence is positioned in the codingregion of the polynucleotide to be expressed towards or at the 5′ end ofthe coding region. The signal sequence may be homologous or heterologousto the polynucleotide of interest and may be homologous or heterologousto the cells to be transfected. Additionally, the signal sequence may bechemically synthesized using methods known in the art.

Any mode of administration of any of the above-described polynucleotidesconstructs can be used so long as the mode results in the expression ofone or more molecules in an amount sufficient to provide a therapeuticeffect. This includes direct needle injection, systemic injection,catheter infusion, biolistic injectors, particle accelerators (i.e.,“gene guns”), gelfoam sponge depots, other commercially available depotmaterials, osmotic pumps (e.g., Alza minipumps), oral or suppositorialsolid (tablet or pill) pharmaceutical formulations, and decanting ortopical applications during surgery. For example, direct injection ofnaked calcium phosphate-precipitated plasmid into rat liver and ratspleen or a protein-coated plasmid into the portal vein has resulted ingene expression of the foreign gene in the rat livers (Kaneda et al.,Science 243:375 (1989)).

A preferred method of local administration is by direct injection.Preferably, a recombinant molecule of the present invention complexedwith a delivery vehicle is administered by direct injection into orlocally within the area of arteries. Administration of a compositionlocally within the area of arteries refers to injecting the compositioncentimeters and preferably, millimeters within arteries.

Another method of local administration is to contact a polynucleotideconstruct of the present invention in or around a surgical wound. Forexample, a patient can undergo surgery and the polynucleotide constructcan be coated on the surface of tissue inside the wound or the constructcan be injected into areas of tissue inside the wound.

Therapeutic compositions useful in systemic administration, includerecombinant molecules of the present invention complexed to a targeteddelivery vehicle of the present invention. Suitable delivery vehiclesfor use with systemic administration comprise liposomes comprisingligands for targeting the vehicle to a particular site. In specificembodiments, suitable delivery vehicles for use with systemicadministration comprise liposomes comprising polypeptides of theinvention for targeting the vehicle to a particular site.

Preferred methods of systemic administration, include intravenousinjection, aerosol, oral and percutaneous (topical) delivery.Intravenous injections can be performed using methods standard in theart. Aerosol delivery can also be performed using methods standard inthe art (see, for example, Stribling et al., Proc. Natl. Acad. Sci. USA189:11277-11281, 1992, which is incorporated herein by reference). Oraldelivery can be performed by complexing a polynucleotide construct ofthe present invention to a carrier capable of withstanding degradationby digestive enzymes in the gut of an animal. Examples of such carriers,include plastic capsules or tablets, such as those known in the art.Topical delivery can be performed by mixing a polynucleotide constructof the present invention with a lipophilic reagent (e.g., DMSO) that iscapable of passing into the skin.

Determining an effective amount of substance to be delivered can dependupon a number of factors including, for example, the chemical structureand biological activity of the substance, the age and weight of theanimal, the precise condition requiring treatment and its severity, andthe route of administration. The frequency of treatments depends upon anumber of factors, such as the amount of polynucleotide constructsadministered per dose, as well as the health and history of the subject.The precise amount, number of doses, and timing of doses will bedetermined by the attending physician or veterinarian.

Therapeutic compositions of the present invention can be administered toany animal, preferably to mammals and birds. Preferred mammals includehumans, dogs, cats, mice, rats, rabbits sheep, cattle, horses and pigs,with humans being particularly preferred.

Biological Activities

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention, can be used in assays to test for one or morebiological activities. If these polynucleotides or polypeptides, oragonists or antagonists of the present invention, do exhibit activity ina particular assay, it is likely that these molecules may be involved inthe diseases associated with the biological activity. Thus, thepolynucleotides and polypeptides, and agonists or antagonists could beused to treat the associated disease.

Members of the secreted family of proteins are believed to be involvedin biological activities associated with, for example, cellularsignaling. Accordingly, compositions of the invention (includingpolynucleotides, polypeptides and antibodies of the invention, andfragments and variants thereof) may be used in diagnosis, prognosis,prevention and/or treatment of diseases and/or disorders associated withaberrant activity of secreted polypeptides.

In preferred embodiments, compositions of the invention (includingpolynucleotides, polypeptides and antibodies of the invention, andfragments and variants thereof) may be used in the diagnosis, prognosis,prevention and/or treatment of diseases and/or disorders relating todiseases and disorders of the endocrine system, the nervous system (See,for example, “Neurological Disorders” section below), and the immunesystem (See, for example, “Immune Activity” section below).

In certain embodiments, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to diagnose and/or prognose diseasesand/or disorders associated with the tissue(s) in which the polypeptideof the invention is expressed including one, two, three, four, five, ormore tissues disclosed in Table 1B.2, column 5 (Tissue DistributionLibrary Code).

Thus, polynucleotides, translation products and antibodies of theinvention are useful in the diagnosis, detection and/or treatment ofdiseases and/or disorders associated with activities that include, butare not limited to, prohormone activation, neurotransmitter activity,cellular signaling, cellular proliferation, cellular differentiation,and cell migration.

More generally, polynucleotides, translation products and antibodiescorresponding to this gene may be useful for the diagnosis, prognosis,prevention and/or treatment of diseases and/or disorders associated withthe following systems.

Immune Activity

Polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in treating,preventing, diagnosing and/or prognosing diseases, disorders, and/orconditions of the immune system, by, for example, activating orinhibiting the proliferation, differentiation, or mobilization(chemotaxis) of immune cells. Immune cells develop through a processcalled hematopoiesis, producing myeloid (platelets, red blood cells,neutrophils, and macrophages) and lymphoid (B and T lymphocytes) cellsfrom pluripotent stem cells. The etiology of these immune diseases,disorders, and/or conditions may be genetic, somatic, such as cancer andsome autoimmune diseases, acquired (e.g., by chemotherapy or toxins), orinfectious. Moreover, polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention can be used as a markeror detector of a particular immune system disease or disorder.

In another embodiment, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to treat diseases and disorders of theimmune system and/or to inhibit or enhance an immune response generatedby cells associated with the tissue(s) in which the polypeptide of theinvention is expressed, including one, two, three, four, five, or moretissues disclosed in Table 1B.2, column 5 (Tissue Distribution LibraryCode).

Polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in treating,preventing, diagnosing, and/or prognosing immunodeficiencies, includingboth congenital and acquired immunodeficiencies. Examples of B cellimmunodeficiencies in which immunoglobulin levels B cell function and/orB cell numbers are decreased include: X-linked agammaglobulinemia(Bruton's disease), X-linked infantile agammaglobulinemia, X-linkedimmunodeficiency with hyper IgM, non X-linked immunodeficiency withhyper IgM, X-linked lymphoproliferative syndrome (XLP),agammaglobulinemia including congenital and acquired agammaglobulinemia,adult onset agammaglobulinemia, late-onset agammaglobulinemia,dysgammaglobulinemia, hypogammaglobulinemia, unspecifiedhypogammaglobulinemia, recessive agammaglobulinemia (Swiss type),Selective IgM deficiency, selective IgA deficiency, selective IgGsubclass deficiencies, IgG subclass deficiency (with or without IgAdeficiency), Ig deficiency with increased IgM, IgG and IgA deficiencywith increased IgM, antibody deficiency with normal or elevated Igs, Igheavy chain deletions, kappa chain deficiency, B celllymphoproliferative disorder (BLPD), common variable immunodeficiency(CVID), common variable immunodeficiency (CVI) (acquired), and transienthypogammaglobulinemia of infancy.

In specific embodiments, ataxia-telangiectasia or conditions associatedwith ataxia-telangiectasia are treated, prevented, diagnosed, and/orprognosing using the polypeptides or polynucleotides of the invention,and/or agonists or antagonists thereof.

Examples of congenital immunodeficiencies in which T cell and/or B cellfunction and/or number is decreased include, but are not limited to:DiGeorge anomaly, severe combined immunodeficiencies (SCID) (including,but not limited to, X-linked SCID, autosomal recessive SCID, adenosinedeaminase deficiency, purine nucleoside phosphorylase (PNP) deficiency,Class II MHC deficiency (Bare lymphocyte syndrome), Wiskott-Aldrichsyndrome, and ataxia telangiectasia), thymic hypoplasia, third andfourth pharyngeal pouch syndrome, 22q11.2 deletion, chronicmucocutaneous candidiasis, natural killer cell deficiency (NK),idiopathic CD4+ T-lymphocytopenia, immunodeficiency with predominant Tcell defect (unspecified), and unspecified immunodeficiency of cellmediated immunity.

In specific embodiments, DiGeorge anomaly or conditions associated withDiGeorge anomaly are treated, prevented, diagnosed, and/or prognosedusing polypeptides or polynucleotides of the invention, or antagonistsor agonists thereof.

Other immunodeficiencies that may be treated, prevented, diagnosed,and/or prognosed using polypeptides or polynucleotides of the invention,and/or agonists or antagonists thereof, include, but are not limited to,chronic granulomatous disease, Chediak-Higashi syndrome, myeloperoxidasedeficiency, leukocyte glucose-6-phosphate dehydrogenase deficiency,X-linked lymphoproliferative syndrome (XLP), leukocyte adhesiondeficiency, complement component deficiencies (including C1, C2, C3, C4,C5, C6, C7, C8 and/or C9 deficiencies), reticular dysgenesis, thymicalymphoplasia-aplasia, immunodeficiency with thymoma, severe congenitalleukopenia, dysplasia with immunodeficiency, neonatal neutropenia, shortlimbed dwarfism, and Nezelof syndrome-combined immunodeficiency withIgs.

In a preferred embodiment, the immunodeficiencies and/or conditionsassociated with the immunodeficiencies recited above are treated,prevented, diagnosed and/or prognosed using polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention.

In a preferred embodiment polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention could be used asan agent to boost immunoresponsiveness among immunodeficientindividuals. In specific embodiments, polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present inventioncould be used as an agent to boost immunoresponsiveness among B celland/or T cell immunodeficient individuals.

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in treating,preventing, diagnosing and/or prognosing autoimmune disorders. Manyautoimmune disorders result from inappropriate recognition of self asforeign material by immune cells. This inappropriate recognition resultsin an immune response leading to the destruction of the host tissue.Therefore, the administration of polynucleotides and polypeptides of theinvention that can inhibit an immune response, particularly theproliferation, differentiation, or chemotaxis of T-cells, may be aneffective therapy in preventing autoimmune disorders.

Autoimmune diseases or disorders that may be treated, prevented,diagnosed and/or prognosed by polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention include, but arenot limited to, one or more of the following: systemic lupuserythematosus, rheumatoid arthritis, ankylosing spondylitis, multiplesclerosis, autoimmune thyroiditis, Hashimoto's thyroiditis, autoimmunehemolytic anemia, hemolytic anemia, thrombocytopenia, autoimmunethrombocytopenia purpura, autoimmune neonatal thrombocytopenia,idiopathic thrombocytopenia purpura, purpura (e.g., Henloch-Scoenleinpurpura), autoimmunocytopenia, Goodpasture's syndrome, Pemphigusvulgaris, myasthenia gravis, Grave's disease (hyperthyroidism), andinsulin-resistant diabetes mellitus.

Additional disorders that are likely to have an autoimmune componentthat may be treated, prevented, and/or diagnosed with the compositionsof the invention include, but are not limited to, type IIcollagen-induced arthritis, antiphospholipid syndrome, dermatitis,allergic encephalomyelitis, myocarditis, relapsing polychondritis,rheumatic heart disease, neuritis, uveitis ophthalmia,polyendocrinopathies, Reiter's Disease, Stiff-Man Syndrome, autoimmunepulmonary inflammation, autism, Guillain-Barre Syndrome, insulindependent diabetes mellitus, and autoimmune inflammatory eye disorders.

Additional disorders that are likely to have an autoimmune componentthat may be treated, prevented, diagnosed and/or prognosed with thecompositions of the invention include, but are not limited to,scleroderma with anti-collagen antibodies (often characterized, e.g., bynucleolar and other nuclear antibodies), mixed connective tissue disease(often characterized, e.g., by antibodies to extractable nuclearantigens (e.g., ribonucleoprotein)), polymyositis (often characterized,e.g., by nonhistone ANA), pernicious anemia (often characterized, e.g.,by antiparietal cell, microsomes, and intrinsic factor antibodies),idiopathic Addison's disease (often characterized, e.g., by humoral andcell-mediated adrenal cytotoxicity, infertility (often characterized,e.g., by antispermatozoal antibodies), glomerulonephritis (oftencharacterized, e.g., by glomerular basement membrane antibodies orimmune complexes), bullous pemphigoid (often characterized, e.g., by IgGand complement in basement membrane), Sjogren's syndrome (oftencharacterized, e.g., by multiple tissue antibodies, and/or a specificnonhistone ANA (SS-B)), diabetes mellitus (often characterized, e.g., bycell-mediated and humoral islet cell antibodies), and adrenergic drugresistance (including adrenergic drug resistance with asthma or cysticfibrosis) (often characterized, e.g., by beta-adrenergic receptorantibodies).

Additional disorders that may have an autoimmune component that may betreated, prevented, diagnosed and/or prognosed with the compositions ofthe invention include, but are not limited to, chronic active hepatitis(often characterized, e.g., by smooth muscle antibodies), primarybiliary cirrhosis (often characterized, e.g., by mitochondriaantibodies), other endocrine gland failure (often characterized, e.g.,by specific tissue antibodies in some cases), vitiligo (oftencharacterized, e.g., by melanocyte antibodies), vasculitis (oftencharacterized, e.g., by Ig and complement in vessel walls and/or lowserum complement), post-MI (often characterized, e.g., by myocardialantibodies), cardiotomy syndrome (often characterized, e.g., bymyocardial antibodies), urticaria (often characterized, e.g., by IgG andIgM antibodies to IgE), atopic dermatitis (often characterized, e.g., byIgG and IgM antibodies to IgE), asthma (often characterized, e.g., byIgG and IgM antibodies to IgE), and many other inflammatory,granulomatous, degenerative, and atrophic disorders.

In a preferred embodiment, the autoimmune diseases and disorders and/orconditions associated with the diseases and disorders recited above aretreated, prevented, diagnosed and/or prognosed using for example,antagonists or agonists, polypeptides or polynucleotides, or antibodiesof the present invention. In a specific preferred embodiment, rheumatoidarthritis is treated, prevented, and/or diagnosed using polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention.

In another specific preferred embodiment, systemic lupus erythematosusis treated, prevented, and/or diagnosed using polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention. In another specific preferred embodiment, idiopathicthrombocytopenia purpura is treated, prevented, and/or diagnosed usingpolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention.

In another specific preferred embodiment IgA nephropathy is treated,prevented, and/or diagnosed using polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present invention.

In a preferred embodiment, the autoimmune diseases and disorders and/orconditions associated with the diseases and disorders recited above aretreated, prevented, diagnosed and/or prognosed using polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention

In preferred embodiments, polypeptides, antibodies, polynucleotidesand/or agonists or antagonists of the present invention are used as aimmunosuppressive agent(s).

Polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in treating,preventing, prognosing, and/or diagnosing diseases, disorders, and/orconditions of hematopoietic cells. Polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present inventioncould be used to increase differentiation and proliferation ofhematopoietic cells, including the pluripotent stem cells, in an effortto treat or prevent those diseases, disorders, and/or conditionsassociated with a decrease in certain (or many) types hematopoieticcells, including but not limited to, leukopenia, neutropenia, anemia,and thrombocytopenia. Alternatively, Polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present inventioncould be used to increase differentiation and proliferation ofhematopoietic cells, including the pluripotent stem cells, in an effortto treat or prevent those diseases, disorders, and/or conditionsassociated with an increase in certain (or many) types of hematopoieticcells, including but not limited to, histiocytosis.

Allergic reactions and conditions, such as asthma (particularly allergicasthma) or other respiratory problems, may also be treated, prevented,diagnosed and/or prognosed using polypeptides, antibodies, orpolynucleotides of the invention, and/or agonists or antagoniststhereof. Moreover, these molecules can be used to treat, prevent,prognose, and/or diagnose anaphylaxis, hypersensitivity to an antigenicmolecule, or blood group incompatibility.

Additionally, polypeptides or polynucleotides of the invention, and/oragonists or antagonists thereof, may be used to treat, prevent, diagnoseand/or prognose IgE-mediated allergic reactions. Such allergic reactionsinclude, but are not limited to, asthma, rhinitis, and eczema. Inspecific embodiments, polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention may be used to modulateIgE concentrations in vitro or in vivo.

Moreover, polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention have uses in the diagnosis,prognosis, prevention, and/or treatment of inflammatory conditions. Forexample, since polypeptides, antibodies, or polynucleotides of theinvention, and/or agonists or antagonists of the invention may inhibitthe activation, proliferation and/or differentiation of cells involvedin an inflammatory response, these molecules can be used to preventand/or treat chronic and acute inflammatory conditions. Suchinflammatory conditions include, but are not limited to, for example,inflammation associated with infection (e.g., septic shock, sepsis, orsystemic inflammatory response syndrome), ischemia-reperfusion injury,endotoxin lethality, complement-mediated hyperacute rejection,nephritis, cytokine or chemokine induced lung injury, inflammatory boweldisease, Crohn's disease, over production of cytokines (e.g., TNF orIL-1.), respiratory disorders (e.g., asthma and allergy);gastrointestinal disorders (e.g., inflammatory bowel disease); cancers(e.g., gastric, ovarian, lung, bladder, liver, and breast); CNSdisorders (e.g., multiple sclerosis; ischemic brain injury and/orstroke, traumatic brain injury, neurodegenerative disorders (e.g.,Parkinson's disease and Alzheimer's disease); AIDS-related dementia; andprion disease); cardiovascular disorders (e.g., atherosclerosis,myocarditis, cardiovascular disease, and cardiopulmonary bypasscomplications); as well as many additional diseases, conditions, anddisorders that are characterized by inflammation (e.g., hepatitis,rheumatoid arthritis, gout, trauma, pancreatitis, sarcoidosis,dermatitis, renal ischemia-reperfusion injury, Grave's disease, systemiclupus erythematosus, diabetes mellitus, and allogenic transplantrejection).

Because inflammation is a fundamental defense mechanism, inflammatorydisorders can effect virtually any tissue of the body. Accordingly,polynucleotides, polypeptides, and antibodies of the invention, as wellas agonists or antagonists thereof, have uses in the treatment oftissue-specific inflammatory disorders, including, but not limited to,adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis,blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis,cholecystitis, chorditis, cochlitis, colitis, conjunctivitis, cystitis,dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis,eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis,gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis,laryngitis, lymphangitis, mastitis, media otitis, meningitis, metritis,mucitis, myocarditis, myosititis, myringitis, nephritis, neuritis,orchitis, osteochondritis, otitis, pericarditis, peritendonitis,peritonitis, pharyngitis, phlebitis, poliomyelitis, prostatitis,pulpitis, retinitis, rhinitis, salpingitis, scleritis,sclerochoroiditis, scrotitis, sinusitis, spondylitis, steatitis,stomatitis, synovitis, syringitis, tendonitis, tonsillitis, urethritis,and vaginitis.

In specific embodiments, polypeptides, antibodies, or polynucleotides ofthe invention, and/or agonists or antagonists thereof, are useful todiagnose, prognose, prevent, and/or treat organ transplant rejectionsand graft-versus-host disease. Organ rejection occurs by host immunecell destruction of the transplanted tissue through an immune response.Similarly, an immune response is also involved in GVHD, but, in thiscase, the foreign transplanted immune cells destroy the host tissues.Polypeptides, antibodies, or polynucleotides of the invention, and/oragonists or antagonists thereof, that inhibit an immune response,particularly the activation, proliferation, differentiation, orchemotaxis of T-cells, may be an effective therapy in preventing organrejection or GVHD. In specific embodiments, polypeptides, antibodies, orpolynucleotides of the invention, and/or agonists or antagoniststhereof, that inhibit an immune response, particularly the activation,proliferation, differentiation, or chemotaxis of T-cells, may be aneffective therapy in preventing experimental allergic and hyperacutexenograft rejection.

In other embodiments, polypeptides, antibodies, or polynucleotides ofthe invention, and/or agonists or antagonists thereof, are useful todiagnose, prognose, prevent, and/or treat immune complex diseases,including, but not limited to, serum sickness, post streptococcalglomerulonephritis, polyarteritis nodosa, and immune complex-inducedvasculitis.

Polypeptides, antibodies, polynucleotides and/or agonists or antagonistsof the invention can be used to treat, detect, and/or prevent infectiousagents. For example, by increasing the immune response, particularlyincreasing the proliferation activation and/or differentiation of Band/or T cells, infectious diseases may be treated, detected, and/orprevented. The immune response may be increased by either enhancing anexisting immune response, or by initiating a new immune response.Alternatively, polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention may also directlyinhibit the infectious agent (refer to section of application listinginfectious agents, etc), without necessarily eliciting an immuneresponse.

In another embodiment, polypeptides, antibodies, polynucleotides and/oragonists or antagonists of the present invention are used as a vaccineadjuvant that enhances immune responsiveness to an antigen. In aspecific embodiment, polypeptides, antibodies, polynucleotides and/oragonists or antagonists of the present invention are used as an adjuvantto enhance tumor-specific immune responses.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an adjuvant to enhance anti-viral immune responses.Anti-viral immune responses that may be enhanced using the compositionsof the invention as an adjuvant, include virus and virus associateddiseases or symptoms described herein or otherwise known in the art. Inspecific embodiments, the compositions of the invention are used as anadjuvant to enhance an immune response to a virus, disease, or symptomselected from the group consisting of: AIDS, meningitis, Dengue, EBV,and hepatitis (e.g., hepatitis B). In another specific embodiment, thecompositions of the invention are used as an adjuvant to enhance animmune response to a virus, disease, or symptom selected from the groupconsisting of: HIV/AIDS, respiratory syncytial virus, Dengue, rotavirus,Japanese B encephalitis, influenza A and B, parainfluenza, measles,cytomegalovirus, rabies, Junin, Chikungunya, Rift Valley Fever, herpessimplex, and yellow fever.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an adjuvant to enhance anti-bacterial or anti-fungal immuneresponses. Anti-bacterial or anti-fungal immune responses that may beenhanced using the compositions of the invention as an adjuvant, includebacteria or fungus and bacteria or fungus associated diseases orsymptoms described herein or otherwise known in the art. In specificembodiments, the compositions of the invention are used as an adjuvantto enhance an immune response to a bacteria or fungus, disease, orsymptom selected from the group consisting of: tetanus, Diphtheria,botulism, and meningitis type B.

In another specific embodiment, the compositions of the invention areused as an adjuvant to enhance an immune response to a bacteria orfungus, disease, or symptom selected from the group consisting of:Vibrio cholerae, Mycobacterium leprae, Salmonella typhi, Salmonellaparatyphi, Meisseria meningitidis, Streptococcus pneumoniae, Group Bstreptococcus, Shigella spp., Enterotoxigenic Escherichia colt,Enterohemorrhagic E. coli, and Borrelia burgdorferi.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an adjuvant to enhance anti-parasitic immune responses.Anti-parasitic immune responses that may be enhanced using thecompositions of the invention as an adjuvant, include parasite andparasite associated diseases or symptoms described herein or otherwiseknown in the art. In specific embodiments, the compositions of theinvention are used as an adjuvant to enhance an immune response to aparasite. In another specific embodiment, the compositions of theinvention are used as an adjuvant to enhance an immune response toPlasmodium (malaria) or Leishmania.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionmay also be employed to treat infectious diseases including silicosis,sarcoidosis, and idiopathic pulmonary fibrosis; for example, bypreventing the recruitment and activation of mononuclear phagocytes.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an antigen for the generation of antibodies to inhibit orenhance immune mediated responses against polypeptides of the invention.

In one embodiment, polypeptides, antibodies, polynucleotides and/oragonists or antagonists of the present invention are administered to ananimal (e.g., mouse, rat, rabbit, hamster, guinea pig, pigs, micro-pig,chicken, camel, goat, horse, cow, sheep, dog, cat, non-human primate,and human, most preferably human) to boost the immune system to produceincreased quantities of one or more antibodies (e.g., IgG, IgA, IgM, andIgE), to induce higher affinity antibody production and immunoglobulinclass switching (e.g., IgG, IgA, IgM, and IgE), and/or to increase animmune response.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a stimulator of B cell responsiveness to pathogens.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an activator of T cells.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent that elevates the immune status of an individualprior to their receipt of immunosuppressive therapies.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to induce higher affinity antibodies.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to increase serum immunoglobulin concentrations.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to accelerate recovery of immunocompromisedindividuals.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to boost immunoresponsiveness among agedpopulations and/or neonates.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an immune system enhancer prior to, during, or after bonemarrow transplant and/or other transplants (e.g., allogeneic orxenogeneic organ transplantation). With respect to transplantation,compositions of the invention may be administered prior to, concomitantwith, and/or after transplantation. In a specific embodiment,compositions of the invention are administered after transplantation,prior to the beginning of recovery of T-cell populations. In anotherspecific embodiment, compositions of the invention are firstadministered after transplantation after the beginning of recovery of Tcell populations, but prior to full recovery of B cell populations.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to boost immunoresponsiveness among individualshaving an acquired loss of B cell function. Conditions resulting in anacquired loss of B cell function that may be ameliorated or treated byadministering the polypeptides, antibodies, polynucleotides and/oragonists or antagonists thereof, include, but are not limited to, HIVInfection, AIDS, bone marrow transplant, and B cell chronic lymphocyticleukemia (CLL).

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to boost immunoresponsiveness among individualshaving a temporary immune deficiency. Conditions resulting in atemporary immune deficiency that may be ameliorated or treated byadministering the polypeptides, antibodies, polynucleotides and/oragonists or antagonists thereof, include, but are not limited to,recovery from viral infections (e.g., influenza), conditions associatedwith malnutrition, recovery from infectious mononucleosis, or conditionsassociated with stress, recovery from measles, recovery from bloodtransfusion, and recovery from surgery.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a regulator of antigen presentation by monocytes, dendriticcells, and/or B-cells. In one embodiment, polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present inventionenhance antigen presentation or antagonizes antigen presentation invitro or in vivo. Moreover, in related embodiments, said enhancement orantagonism of antigen presentation may be useful as an anti-tumortreatment or to modulate the immune system.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as an agent to direct an individual's immune system towardsdevelopment of a humoral response (i.e. TH2) as opposed to a TH1cellular response.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a means to induce tumor proliferation and thus make it moresusceptible to anti-neoplastic agents. For example, multiple myeloma isa slowly dividing disease and is thus refractory to virtually allanti-neoplastic regimens. If these cells were forced to proliferate morerapidly their susceptibility profile would likely change.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a stimulator of B cell production in pathologies such asAIDS, chronic lymphocyte disorder and/or Common VariableImmunodificiency.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a therapy for generation and/or regeneration of lymphoidtissues following surgery, trauma or genetic defect. In another specificembodiment, polypeptides, antibodies, polynucleotides and/or agonists orantagonists of the present invention are used in the pretreatment ofbone marrow samples prior to transplant.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a gene-based therapy for genetically inherited disordersresulting in immuno-incompetence/immunodeficiency such as observed amongSCID patients.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a means of activating monocytes/macrophages to defendagainst parasitic diseases that effect monocytes such as Leishmania.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a means of regulating secreted cytokines that are elicitedby polypeptides of the invention.

In another embodiment, polypeptides, antibodies, polynucleotides and/oragonists or antagonists of the present invention are used in one or moreof the applications decribed herein, as they may apply to veterinarymedicine.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a means of blocking various aspects of immune responses toforeign agents or self. Examples of diseases or conditions in whichblocking of certain aspects of immune responses may be desired includeautoimmune disorders such as lupus, and arthritis, as well asimmunoresponsiveness to skin allergies, inflammation, bowel disease,injury and diseases/disorders associated with pathogens.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a therapy for preventing the B cell proliferation and Igsecretion associated with autoimmune diseases such as idiopathicthrombocytopenic purpura, systemic lupus erythematosus and multiplesclerosis.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a inhibitor of B and/or T cell migration in endothelialcells. This activity disrupts tissue architecture or cognate responsesand is useful, for example in disrupting immune responses, and blockingsepsis.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a therapy for chronic hypergammaglobulinemia evident in suchdiseases as monoclonal gammopathy of undetermined significance (MGUS),Waldenstrom's disease, related idiopathic monoclonal gammopathies, andplasmacytomas.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionmay be employed for instance to inhibit polypeptide chemotaxis andactivation of macrophages and their precursors, and of neutrophils,basophils, B lymphocytes and some T-cell subsets, e.g., activated andCD8 cytotoxic T cells and natural killer cells, in certain autoimmuneand chronic inflammatory and infective diseases. Examples of autoimmunediseases are described herein and include multiple sclerosis, andinsulin-dependent diabetes.

The polypeptides, antibodies, polynucleotides and/or agonists orantagonists of the present invention may also be employed to treatidiopathic hyper-eosinophilic syndrome by, for example, preventingeosinophil production and migration.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used to enhance or inhibit complement mediated cell lysis.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used to enhance or inhibit antibody dependent cellular cytotoxicity.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionmay also be employed for treating atherosclerosis, for example, bypreventing monocyte infiltration in the artery wall.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionmay be employed to treat adult respiratory distress syndrome (ARDS).

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionmay be useful for stimulating wound and tissue repair, stimulatingangiogenesis, and/or stimulating the repair of vascular or lymphaticdiseases or disorders. Additionally, agonists and antagonists of theinvention may be used to stimulate the regeneration of mucosal surfaces.

In a specific embodiment, polynucleotides or polypeptides, and/oragonists thereof are used to diagnose, prognose, treat, and/or prevent adisorder characterized by primary or acquired immunodeficiency,deficient serum immunoglobulin production, recurrent infections, and/orimmune system dysfunction. Moreover, polynucleotides or polypeptides,and/or agonists thereof may be used to treat or prevent infections ofthe joints, bones, skin, and/or parotid glands, blood-borne infections(e.g., sepsis, meningitis, septic arthritis, and/or osteomyelitis),autoimmune diseases (e.g., those disclosed herein), inflammatorydisorders, and malignancies, and/or any disease or disorder or conditionassociated with these infections, diseases, disorders and/ormalignancies) including, but not limited to, CVID, other primary immunedeficiencies, HIV disease, CLL, recurrent bronchitis, sinusitis, otitismedia, conjunctivitis, pneumonia, hepatitis, meningitis, herpes zoster(e.g., severe herpes zoster), and/or pneumocystis carnii. Other diseasesand disorders that may be prevented, diagnosed, prognosed, and/ortreated with polynucleotides or polypeptides, and/or agonists of thepresent invention include, but are not limited to, HIV infection,HTLV-BLV infection, lymphopenia, phagocyte bactericidal dysfunctionanemia, thrombocytopenia, and hemoglobinuria.

In another embodiment, polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention are used to treat,and/or diagnose an individual having common variable immunodeficiencydisease (“CVID”; also known as “acquired agammaglobulinemia” and“acquired hypogammaglobulinemia”) or a subset of this disease.

In a specific embodiment, polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be used todiagnose, prognose, prevent, and/or treat cancers or neoplasms includingimmune cell or immune tissue-related cancers or neoplasms. Examples ofcancers or neoplasms that may be prevented, diagnosed, or treated bypolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention include, but are not limited to,acute myelogenous leukemia, chronic myelogenous leukemia, Hodgkin'sdisease, non-Hodgkin's lymphoma, acute lymphocytic anemia (ALL) Chroniclymphocyte leukemia, plasmacytomas, multiple myeloma, Burkitt'slymphoma, EBV-transformed diseases, and/or diseases and disordersdescribed in the section entitled “Hyperproliferative Disorders”elsewhere herein.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a therapy for decreasing cellular proliferation of LargeB-cell Lymphomas.

In another specific embodiment, polypeptides, antibodies,polynucleotides and/or agonists or antagonists of the present inventionare used as a means of decreasing the involvement of B cells and Igassociated with Chronic Myelogenous Leukemia.

In specific embodiments, the compositions of the invention are used asan agent to boost immunoresponsiveness among B cell immunodeficientindividuals, such as, for example, an individual who has undergone apartial or complete splenectomy.

Antagonists of the invention include, for example, binding and/orinhibitory antibodies, antisense nucleic acids, ribozymes or solubleforms of the polypeptides of the present invention (e.g., Fc fusionprotein; see, e.g., Example 9). Agonists of the invention include, forexample, binding or stimulatory antibodies, and soluble forms of thepolypeptides (e.g., Fc fusion proteins; see, e.g., Example 9).polypeptides, antibodies, polynucleotides and/or agonists or antagonistsof the present invention may be employed in a composition with apharmaceutically acceptable carrier, e.g., as described herein.

In another embodiment, polypeptides, antibodies, polynucleotides and/oragonists or antagonists of the present invention are administered to ananimal (including, but not limited to, those listed above, and alsoincluding transgenic animals) incapable of producing functionalendogenous antibody molecules or having an otherwise compromisedendogenous immune system, but which is capable of producing humanimmunoglobulin molecules by means of a reconstituted or partiallyreconstituted immune system from another animal (see, e.g., publishedPCT Application Nos. WO98/24893, WO/9634096, WO/9633735, andWO/9110741). Administration of polypeptides, antibodies, polynucleotidesand/or agonists or antagonists of the present invention to such animalsis useful for the generation of monoclonal antibodies against thepolypeptides, antibodies, polynucleotides and/or agonists or antagonistsof the present invention.

Blood-Related Disorders

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be used to modulate hemostatic(the stopping of bleeding) or thrombolytic (clot dissolving) activity.For example, by increasing hemostatic or thrombolytic activity,polynucleotides or polypeptides, and/or agonists or antagonists of thepresent invention could be used to treat or prevent blood coagulationdiseases, disorders, and/or conditions (e.g., afibrinogenemia, factordeficiencies, hemophilia), blood platelet diseases, disorders, and/orconditions (e.g., thrombocytopenia), or wounds resulting from trauma,surgery, or other causes. Alternatively, polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present invention thatcan decrease hemostatic or thrombolytic activity could be used toinhibit or dissolve clotting. These molecules could be important in thetreatment or prevention of heart attacks (infarction), strokes, orscarring.

In specific embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be used toprevent, diagnose, prognose, and/or treat thrombosis, arterialthrombosis, venous thrombosis, thromboembolism, pulmonary embolism,atherosclerosis, myocardial infarction, transient ischemic attack,unstable angina. In specific embodiments, the polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention may be used for the prevention of occulsion of saphenousgrafts, for reducing the risk of periprocedural thrombosis as mightaccompany angioplasty procedures, for reducing the risk of stroke inpatients with atrial fibrillation including nonrheumatic atrialfibrillation, for reducing the risk of embolism associated withmechanical heart valves and or mitral valves disease. Other uses for thepolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention, include, but are not limited to,the prevention of occlusions in extrcorporeal devices (e.g.,intravascular canulas, vascular access shunts in hemodialysis patients,hemodialysis machines, and cardiopulmonary bypass machines).

In another embodiment, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to prevent, diagnose, prognose, and/ortreat diseases and disorders of the blood and/or blood forming organsassociated with the tissue(s) in which the polypeptide of the inventionis expressed, including one, two, three, four, five, or more tissuesdisclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be used to modulatehematopoietic activity (the formation of blood cells). For example, thepolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be used to increase thequantity of all or subsets of blood cells, such as, for example,erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g.,basophils, eosinophils, neutrophils, mast cells, macrophages) andplatelets. The ability to decrease the quantity of blood cells orsubsets of blood cells may be useful in the prevention, detection,diagnosis and/or treatment of anemias and leukopenias described below.Alternatively, the polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention may be used to decreasethe quantity of all or subsets of blood cells, such as, for example,erythrocytes, lymphocytes (B or T cells), myeloid cells (e.g.,basophils, eosinophils, neutrophils, mast cells, macrophages) andplatelets. The ability to decrease the quantity of blood cells orsubsets of blood cells may be useful in the prevention, detection,diagnosis and/or treatment of leukocytoses, such as, for exampleeosinophilia.

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be used to prevent, treat, ordiagnose blood dyscrasia.

Anemias are conditions in which the number of red blood cells or amountof hemoglobin (the protein that carries oxygen) in them is below normal.Anemia may be caused by excessive bleeding, decreased red blood cellproduction, or increased red blood cell destruction (hemolysis). Thepolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in treating,preventing, and/or diagnosing anemias. Anemias that may be treatedprevented or diagnosed by the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention include irondeficiency anemia, hypochromic anemia, microcytic anemia, chlorosis,hereditary siderob; astic anemia, idiopathic acquired sideroblasticanemia, red cell aplasia, megaloblastic anemia (e.g., pernicious anemia,(vitamin B12 deficiency) and folic acid deficiency anemia), aplasticanemia, hemolytic anemias (e.g., autoimmune helolytic anemia,microangiopathic hemolytic anemia, and paroxysmal nocturnalhemoglobinuria). The polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention may be useful intreating, preventing, and/or diagnosing anemias associated with diseasesincluding but not limited to, anemias associated with systemic lupuserythematosus, cancers, lymphomas, chronic renal disease, and enlargedspleens. The polynucleotides, polypeptides, antibodies, and/or agonistsor antagonists of the present invention may be useful in treating,preventing, and/or diagnosing anemias arising from drug treatments suchas anemias associated with methyldopa, dapsone, and/or sulfadrugs.Additionally, rhe polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention may be useful intreating, preventing, and/or diagnosing anemias associated with abnormalred blood cell architecture including but not limited to, hereditaryspherocytosis, hereditary elliptocytosis, glucose-6-phosphatedehydrogenase deficiency, and sickle cell anemia.

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in treating,preventing, and/or diagnosing hemoglobin abnormalities, (e.g., thoseassociated with sickle cell anemia, hemoglobin C disease, hemoglobin S-Cdisease, and hemoglobin E disease). Additionally, the polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention may be useful in diagnosing, prognosing, preventing, and/ortreating thalassemias, including, but not limited to major and minorforms of alpha-thalassemia and beta-thalassemia.

In another embodiment, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful indiagnosing, prognosing, preventing, and/or treating bleeding disordersincluding, but not limited to, thrombocytopenia (e.g., idiopathicthrombocytopenic purpura, and thrombotic thrombocytopenic purpura), VonWillebrand's disease, hereditary platelet disorders (e.g., storage pooldisease such as Chediak-Higashi and Hermansky-Pudlak syndromes,thromboxane A2 dysfunction, thromboasthenia, and Bemard-Souliersyndrome), hemolytic-uremic syndrome, hemophelias such as hemophelia Aor Factor VII deficiency and Christmas disease or Factor IX deficiency,Hereditary Hemorhhagic Telangiectsia, also known as Rendu-Osler-Webersyndrome, allergic purpura (Henoch Schonlein purpura) and disseminatedintravascular coagulation.

The effect of the polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention on the clotting time ofblood may be monitored using any of the clotting tests known in the artincluding, but not limited to, whole blood partial thromboplastin time(PTT), the activated partial thromboplastin time (aPTT), the activatedclotting time (ACT), the recalcified activated clotting time, or theLee-White Clotting time.

Several diseases and a variety of drugs can cause platelet dysfunction.Thus, in a specific embodiment, the polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present invention maybe useful in diagnosing, prognosing, preventing, and/or treatingacquired platelet dysfunction such as platelet dysfunction accompanyingkidney failure, leukemia, multiple myeloma, cirrhosis of the liver, andsystemic lupus erythematosus as well as platelet dysfunction associatedwith drug treatments, including treatment with aspirin, ticlopidine,nonsteroidal anti-inflammatory drugs (used for arthritis, pain, andsprains), and penicillin in high doses.

In another embodiment, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful indiagnosing, prognosing, preventing, and/or treating diseases anddisorders characterized by or associated with increased or decreasednumbers of white blood cells. Leukopenia occurs when the number of whiteblood cells decreases below normal. Leukopenias include, but are notlimited to, neutropenia and lymphocytopenia. An increase in the numberof white blood cells compared to normal is known as leukocytosis. Thebody generates increased numbers of white blood cells during infection.Thus, leukocytosis may simply be a normal physiological parameter thatreflects infection. Alternatively, leukocytosis may be an indicator ofinjury or other disease such as cancer. Leokocytoses, include but arenot limited to, eosinophilia, and accumulations of macrophages. Inspecific embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful indiagnosing, prognosing, preventing, and/or treating leukopenia. In otherspecific embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful indiagnosing, prognosing, preventing, and/or treating leukocytosis.

Leukopenia may be a generalized decreased in all types of white bloodcells, or may be a specific depletion of particular types of white bloodcells. Thus, in specific embodiments, the polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present invention maybe useful in diagnosing, prognosing, preventing, and/or treatingdecreases in neutrophil numbers, known as neutropenia. Neutropenias thatmay be diagnosed, prognosed, prevented, and/or treated by thepolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention include, but are not limited to,infantile genetic agranulocytosis, familial neutropenia, cyclicneutropenia, neutropenias resulting from or associated with dietarydeficiencies (e.g., vitamin B 12 deficiency or folic acid deficiency),neutropenias resulting from or associated with drug treatments (e.g.,antibiotic regimens such as penicillin treatment, sulfonamide treatment,anticoagulant treatment, anticonvulsant drugs, anti-thyroid drugs, andcancer chemotherapy), and neutropenias resulting from increasedneutrophil destruction that may occur in association with some bacterialor viral infections, allergic disorders, autoimmune diseases, conditionsin which an individual has an enlarged spleen (e.g., Felty syndrome,malaria and sarcoidosis), and some drug treatment regimens.

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in diagnosing,prognosing, preventing, and/or treating lymphocytopenias (decreasednumbers of B and/or T lymphocytes), including, but not limitedlymphocytopenias resulting from or associated with stress, drugtreatments (e.g., drug treatment with corticosteroids, cancerchemotherapies, and/or radiation therapies), AIDS infection and/or otherdiseases such as, for example, cancer, rheumatoid arthritis, systemiclupus erythematosus, chronic infections, some viral infections and/orhereditary disorders (e.g., DiGeorge syndrome, Wiskott-Aldrich Syndome,severe combined immunodeficiency, ataxia telangiectsia).

The polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful in diagnosing,prognosing, preventing, and/or treating diseases and disordersassociated with macrophage numbers and/or macrophage function including,but not limited to, Gaucher's disease, Niemann-Pick disease,Letterer-Siwe disease and Hand-Schuller-Christian disease.

In another embodiment, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful indiagnosing, prognosing, preventing, and/or treating diseases anddisorders associated with eosinophil numbers and/or eosinophil functionincluding, but not limited to, idiopathic hypereosinophilic syndrome,eosinophilia-myalgia syndrome, and Hand-Schuller-Christian disease.

In yet another embodiment, the polynucleotides, polypeptides,antibodies, and/or agonists or antagonists of the present invention maybe useful in diagnosing, prognosing, preventing, and/or treatingleukemias and lymphomas including, but not limited to, acute lymphocytic(lymphpblastic) leukemia (ALL), acute myeloid (myelocytic, myelogenous,myeloblastic, or myelomonocytic) leukemia, chronic lymphocytic leukemia(e.g., B cell leukemias, T cell leukemias, Sezary syndrome, and Hairycell leukenia), chronic myelocytic (myeloid, myelogenous, orgranulocytic) leukemia, Hodgkin's lymphoma, non-hodgkin's lymphoma,Burkitt's lymphoma, and mycosis fungoides.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful indiagnosing, prognosing, preventing, and/or treating diseases anddisorders of plasma cells including, but not limited to, plasma celldyscrasias, monoclonal gammaopathies, monoclonal gammopathies ofundetermined significance, multiple myeloma, macroglobulinemia,Waldenstrom's macroglobulinemia, cryoglobulinemia, and Raynaud'sphenomenon.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful intreating, preventing, and/or diagnosing myeloproliferative disorders,including but not limited to, polycythemia vera, relative polycythemia,secondary polycythemia, myelofibrosis, acute myelofibrosis, agnogenicmyelod metaplasia, thrombocythemia, (including both primary and secondaythrombocythemia) and chronic myelocytic leukemia.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful asa treatment prior to surgery, to increase blood cell production.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful asan agent to enhance the migration, phagocytosis, superoxide production,antibody dependent cellular cytotoxicity of neutrophils, eosionophilsand macrophages.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful asan agent to increase the number of stem cells in circulation prior tostem cells pheresis. In another specific embodiment, thepolynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention may be useful as an agent toincrease the number of stem cells in circulation prior to plateletpheresis.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful asan agent to increase cytokine production.

In other embodiments, the polynucleotides, polypeptides, antibodies,and/or agonists or antagonists of the present invention may be useful inpreventing, diagnosing, and/or treating primary hematopoietic disorders.

Hyperproliferative Disorders

In certain embodiments, polynucleotides or polypeptides, or agonists orantagonists of the present invention can be used to treat or detecthyperproliferative disorders, including neoplasms. Polynucleotides orpolypeptides, or agonists or antagonists of the present invention mayinhibit the proliferation of the disorder through direct or indirectinteractions. Alternatively, Polynucleotides or polypeptides, oragonists or antagonists of the present invention may proliferate othercells which can inhibit the hyperproliferative disorder.

For example, by increasing an immune response, particularly increasingantigenic qualities of the hyperproliferative disorder or byproliferating, differentiating, or mobilizing T-cells,hyperproliferative disorders can be treated. This immune response may beincreased by either enhancing an existing immune response, or byinitiating a new immune response. Alternatively, decreasing an immuneresponse may also be a method of treating hyperproliferative disorders,such as a chemotherapeutic agent.

Examples of hyperproliferative disorders that can be treated or detectedby polynucleotides or polypeptides, or agonists or antagonists of thepresent invention include, but are not limited to neoplasms located inthe: colon, abdomen, bone, breast, digestive system, liver, pancreas,peritoneum, endocrine glands (adrenal, parathyroid, pituitary,testicles, ovary, thymus, thyroid), eye, head and neck, nervous (centraland peripheral), lymphatic system, pelvis, skin, soft tissue, spleen,thorax, and urogenital tract.

Similarly, other hyperproliferative disorders can also be treated ordetected by polynucleotides or polypeptides, or agonists or antagonistsof the present invention. Examples of such hyperproliferative disordersinclude, but are not limited to: Acute Childhood Lymphoblastic Leukemia,Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute MyeloidLeukemia, Adrenocortical Carcinoma, Adult (Primary) HepatocellularCancer, Adult (Primary) Liver Cancer, Adult Acute Lymphocytic Leukemia,Adult Acute Myeloid Leukemia, Adult Hodgkin's Disease, Adult Hodgkin'sLymphoma, Adult Lymphocytic Leukemia, Adult Non-Hodgkin's Lymphoma,Adult Primary Liver Cancer, Adult Soft Tissue Sarcoma, AIDS-RelatedLymphoma, AIDS-Related Malignancies, Anal Cancer, Astrocytoma, Bile DuctCancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumors,Breast Cancer, Cancer of the Renal Pelvis and Ureter, Central NervousSystem (Primary) Lymphoma, Central Nervous System Lymphoma, CerebellarAstrocytoma, Cerebral Astrocytoma, Cervical Cancer, Childhood (Primary)Hepatocellular Cancer, Childhood (Primary) Liver Cancer, Childhood AcuteLymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, ChildhoodBrain Stem Glioma, Childhood Cerebellar Astrocytoma, Childhood CerebralAstrocytoma, Childhood Extracranial Germ Cell Tumors, ChildhoodHodgkin's Disease, Childhood Hodgkin's Lymphoma, Childhood Hypothalamicand Visual Pathway Glioma, Childhood Lymphoblastic Leukemia, ChildhoodMedulloblastoma, Childhood Non-Hodgkin's Lymphoma, Childhood Pineal andSupratentorial Primitive Neuroectodermal Tumors, Childhood Primary LiverCancer, Childhood Rhabdomyosarcoma, Childhood Soft Tissue Sarcoma,Childhood Visual Pathway and Hypothalamic Glioma, Chronic LymphocyticLeukemia, Chronic Myelogenous Leukemia, Colon Cancer, Cutaneous T-CellLymphoma, Endocrine Pancreas Islet Cell Carcinoma, Endometrial Cancer,Ependymoma, Epithelial Cancer, Esophageal Cancer, Ewing's Sarcoma andRelated Tumors, Exocrine Pancreatic Cancer, Extracranial Germ CellTumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, EyeCancer, Female Breast Cancer, Gaucher's Disease, Gallbladder Cancer,Gastric Cancer, Gastrointestinal Carcinoid Tumor, GastrointestinalTumors, Germ Cell Tumors, Gestational Trophoblastic Tumor, Hairy CellLeukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin'sDisease, Hodgkin's Lymphoma, Hypergammaglobulinemia, HypopharyngealCancer, Intestinal Cancers, Intraocular Melanoma, Islet Cell Carcinoma,Islet Cell Pancreatic Cancer, Kaposi's Sarcoma, Kidney Cancer, LaryngealCancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer,Lymphoproliferative Disorders, Macroglobulinemia, Male Breast Cancer,Malignant Mesothelioma, Malignant Thymoma, Medulloblastoma, Melanoma,Mesothelioma, Metastatic Occult Primary Squamous Neck Cancer, MetastaticPrimary Squamous Neck Cancer, Metastatic Squamous Neck Cancer, MultipleMyeloma, Multiple Myeloma/Plasma Cell Neoplasm, MyelodysplasticSyndrome, Myelogenous Leukemia, Myeloid Leukemia, MyeloproliferativeDisorders, Nasal Cavity and Paranasal Sinus Cancer, NasopharyngealCancer, Neuroblastoma, Non-Hodgkin's Lymphoma During Pregnancy,Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Occult PrimaryMetastatic Squamous Neck Cancer, Oropharyngeal Cancer, Osteo-/MalignantFibrous Sarcoma, Osteosarcoma/Malignant Fibrous Histiocytoma,Osteosarcoma/Malignant Fibrous Histiocytoma of Bone, Ovarian EpithelialCancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor,Pancreatic Cancer, Paraproteinemias, Purpura, Parathyroid Cancer, PenileCancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/MultipleMyeloma, Primary Central Nervous System Lymphoma, Primary Liver Cancer,Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis andUreter Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer,Sarcoidosis Sarcomas, Sezary Syndrome, Skin Cancer, Small Cell LungCancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous NeckCancer, Stomach Cancer, Supratentorial Primitive Neuroectodermal andPineal Tumors, T-Cell Lymphoma, Testicular Cancer, Thymoma, ThyroidCancer, Transitional Cell Cancer of the Renal Pelvis and Ureter,Transitional Renal Pelvis and Ureter Cancer, Trophoblastic Tumors,Ureter and Renal Pelvis Cell Cancer, Urethral Cancer, Uterine Cancer,Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma,Vulvar Cancer, Waldenstrom's Macroglobulinemia, Wilms' Tumor, and anyother hyperproliferative disease, besides neoplasia, located in an organsystem listed above.

In another preferred embodiment, polynucleotides or polypeptides, oragonists or antagonists of the present invention are used to diagnose,prognose, prevent, and/or treat premalignant conditions and to preventprogression to a neoplastic or malignant state, including but notlimited to those disorders described above. Such uses are indicated inconditions known or suspected of preceding progression to neoplasia orcancer, in particular, where non-neoplastic cell growth consisting ofhyperplasia, metaplasia, or most particularly, dysplasia has occurred(for review of such abnormal growth conditions, see Robbins and Angell,1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp.68-79.)

Hyperplasia is a form of controlled cell proliferation, involving anincrease in cell number in a tissue or organ, without significantalteration in structure or function. Hyperplastic disorders which can bediagnosed, prognosed, prevented, and/or treated with compositions of theinvention (including polynucleotides, polypeptides, agonists orantagonists) include, but are not limited to, angiofollicularmediastinal lymph node hyperplasia, angiolymphoid hyperplasia witheosinophilia, atypical melanocytic hyperplasia, basal cell hyperplasia,benign giant lymph node hyperplasia, cementum hyperplasia, congenitaladrenal hyperplasia, congenital sebaceous hyperplasia, cystichyperplasia, cystic hyperplasia of the breast, denture hyperplasia,ductal hyperplasia, endometrial hyperplasia, fibromuscular hyperplasia,focal epithelial hyperplasia, gingival hyperplasia, inflammatory fibroushyperplasia, inflammatory papillary hyperplasia, intravascular papillaryendothelial hyperplasia, nodular hyperplasia of prostate, nodularregenerative hyperplasia, pseudoepitheliomatous hyperplasia, senilesebaceous hyperplasia, and verrucous hyperplasia.

Metaplasia is a form of controlled cell growth in which one type ofadult or fully differentiated cell substitutes for another type of adultcell. Metaplastic disorders which can be diagnosed, prognosed,prevented, and/or treated with compositions of the invention (includingpolynucleotides, polypeptides, agonists or antagonists) include, but arenot limited to, agnogenic myeloid metaplasia, apocrine metaplasia,atypical metaplasia, autoparenchymatous metaplasia, connective tissuemetaplasia, epithelial metaplasia, intestinal metaplasia, metaplasticanemia, metaplastic ossification, metaplastic polyps, myeloidmetaplasia, primary myeloid metaplasia, secondary myeloid metaplasia,squamous metaplasia, squamous metaplasia of amnion, and symptomaticmyeloid metaplasia.

Dysplasia is frequently a forerunner of cancer, and is found mainly inthe epithelia; it is the most disorderly form of non-neoplastic cellgrowth, involving a loss in individual cell uniformity and in thearchitectural orientation of cells. Dysplastic cells often haveabnormally large, deeply stained nuclei, and exhibit pleomorphism.Dysplasia characteristically occurs where there exists chronicirritation or inflammation. Dysplastic disorders which can be diagnosed,prognosed, prevented, and/or treated with compositions of the invention(including polynucleotides, polypeptides, agonists or antagonists)include, but are not limited to, anhidrotic ectodermal dysplasia,anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigitaldysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervicaldysplasia, chondroectodermal dysplasia, cleidocranial dysplasia,congenital ectodermal dysplasia, craniodiaphysial dysplasia,craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentindysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia,encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia,dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata,epithelial dysplasia, faciodigitogenital dysplasia, familial fibrousdysplasia of jaws, familial white folded dysplasia, fibromusculardysplasia, fibrous dysplasia of bone, florid osseous dysplasia,hereditary renal-retinal dysplasia, hidrotic ectodermal dysplasia,hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammarydysplasia, mandibulofacial dysplasia, metaphysial dysplasia, Mondinidysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia,multiple epiphysial dysplasia, oculoauriculovertebral dysplasia,oculodentodigital dysplasia, oculovertebral dysplasia, odontogenicdysplasia, ophthalmomandibulomelic dysplasia, periapical cementaldysplasia, polyostotic fibrous dysplasia, pseudoachondroplasticspondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia,spondyloepiphysial dysplasia, and ventriculoradial dysplasia.

Additional pre-neoplastic disorders which can be diagnosed, prognosed,prevented, and/or treated with compositions of the invention (includingpolynucleotides, polypeptides, agonists or antagonists) include, but arenot limited to, benign dysproliferative disorders (e.g., benign tumors,fibrocystic conditions, tissue hypertrophy, intestinal polyps, colonpolyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen'sdisease, Farmer's Skin, solar cheilitis, and solar keratosis.

In another embodiment, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to diagnose and/or prognose disordersassociated with the tissue(s) in which the polypeptide of the inventionis expressed, including one, two, three, four, five, or more tissuesdisclosed in Table 1B.2, column 5 (Tissue Distribution Library Code).

In another embodiment, polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention conjugated to a toxinor a radioactive isotope, as described herein, may be used to treatcancers and neoplasms, including, but not limited to those describedherein. In a further preferred embodiment, polynucleotides,polypeptides, antibodies, and/or agonists or antagonists of the presentinvention conjugated to a toxin or a radioactive isotope, as describedherein, may be used to treat acute myelogenous leukemia.

Additionally, polynucleotides, polypeptides, and/or agonists orantagonists of the invention may affect apoptosis, and therefore, wouldbe useful in treating a number of diseases associated with increasedcell survival or the inhibition of apoptosis. For example, diseasesassociated with increased cell survival or the inhibition of apoptosisthat could be diagnosed, prognosed, prevented, and/or treated bypolynucleotides, polypeptides, and/or agonists or antagonists of theinvention, include cancers (such as follicular lymphomas, carcinomaswith p53 mutations, and hormone-dependent tumors, including, but notlimited to colon cancer, cardiac tumors, pancreatic cancer, melanoma,retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicularcancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma,endothelioma, osteoblastoma, osteoclastoma, osteosarcoma,chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi'ssarcoma and ovarian cancer); autoimmune disorders such as, multiplesclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliarycirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemiclupus erythematosus and immune-related glomerulonephritis and rheumatoidarthritis) and viral infections (such as herpes viruses, pox viruses andadenoviruses), inflammation, graft v. host disease, acute graftrejection, and chronic graft rejection.

In preferred embodiments, polynucleotides, polypeptides, and/or agonistsor antagonists of the invention are used to inhibit growth, progression,and/or metastasis of cancers, in particular those listed above.

Additional diseases or conditions associated with increased cellsurvival that could be diagnosed, prognosed, prevented, and/or treatedby polynucleotides, polypeptides, and/or agonists or antagonists of theinvention, include, but are not limited to, progression, and/ormetastases of malignancies and related disorders such as leukemia(including acute leukemias (e.g., acute lymphocytic leukemia, acutemyelocytic leukemia (including myeloblastic, promyelocytic,myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias(e.g., chronic myelocytic (granulocytic) leukemia and chroniclymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin'sdisease and non-Hodgkin's disease), multiple myeloma, Waldenstrom'smacroglobulinemia, heavy chain disease, and solid tumors including, butnot limited to, sarcomas and carcinomas such as fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, emangioblastoma, acousticneuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, andretinoblastoma.

Diseases associated with increased apoptosis that could be diagnosed,prognosed, prevented, and/or treated by polynucleotides, polypeptides,and/or agonists or antagonists of the invention, include AIDS;neurodegenerative disorders (such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellardegeneration and brain tumor or prior associated disease); autoimmunedisorders (such as, multiple sclerosis, Sjogren's syndrome, Hashimoto'sthyroiditis, biliary cirrhosis, Behcet's disease, Crohn's disease,polymyositis, systemic lupus erythematosus and immune-relatedglomerulonephritis and rheumatoid arthritis) myelodysplastic syndromes(such as aplastic anemia), graft v. host disease, ischemic injury (suchas that caused by myocardial infarction, stroke and reperfusion injury),liver injury (e.g., hepatitis related liver injury, ischemia/reperfusioninjury, cholestosis (bile duct injury) and liver cancer); toxin-inducedliver disease (such as that caused by alcohol), septic shock, cachexiaand anorexia.

Hyperproliferative diseases and/or disorders that could be diagnosed,prognosed, prevented, and/or treated by polynucleotides, polypeptides,and/or agonists or antagonists of the invention, include, but are notlimited to, neoplasms located in the liver, abdomen, bone, breast,digestive system, pancreas, peritoneum, endocrine glands (adrenal,parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, headand neck, nervous system (central and peripheral), lymphatic system,pelvis, skin, soft tissue, spleen, thorax, and urogenital tract.

Similarly, other hyperproliferative disorders can also be diagnosed,prognosed, prevented, and/or treated by polynucleotides, polypeptides,and/or agonists or antagonists of the invention. Examples of suchhyperproliferative disorders include, but are not limited to:hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemias,purpura, sarcoidosis, Sezary Syndrome, Waldenstron's macroglobulinemia,Gaucher's Disease, histiocytosis, and any other hyperproliferativedisease, besides neoplasia, located in an organ system listed above.

Another preferred embodiment utilizes polynucleotides of the presentinvention to inhibit aberrant cellular division, by gene therapy usingthe present invention, and/or protein fusions or fragments thereof.

Thus, the present invention provides a method for treating cellproliferative disorders by inserting into an abnormally proliferatingcell a polynucleotide of the present invention, wherein saidpolynucleotide represses said expression.

Another embodiment of the present invention provides a method oftreating cell-proliferative disorders in individuals comprisingadministration of one or more active gene copies of the presentinvention to an abnormally proliferating cell or cells. In a preferredembodiment, polynucleotides of the present invention is a DNA constructcomprising a recombinant expression vector effective in expressing a DNAsequence encoding said polynucleotides. In another preferred embodimentof the present invention, the DNA construct encoding the polynucleotidesof the present invention is inserted into cells to be treated utilizinga retrovirus, or more preferably an adenoviral vector (See G J. Nabel,et. al., PNAS 1999 96: 324-326, which is hereby incorporated byreference). In a most preferred embodiment, the viral vector isdefective and will not transform non-proliferating cells, onlyproliferating cells. Moreover, in a preferred embodiment, thepolynucleotides of the present invention inserted into proliferatingcells either alone, or in combination with or fused to otherpolynucleotides, can then be modulated via an external stimulus (i.e.magnetic, specific small molecule, chemical, or drug administration,etc.), which acts upon the promoter upstream of said polynucleotides toinduce expression of the encoded protein product. As such the beneficialtherapeutic affect of the present invention may be expressly modulated(i.e. to increase, decrease, or inhibit expression of the presentinvention) based upon said external stimulus.

Polynucleotides of the present invention may be useful in repressingexpression of oncogenic genes or antigens. By “repressing expression ofthe oncogenic genes” is intended the suppression of the transcription ofthe gene, the degradation of the gene transcript (pre-message RNA), theinhibition of splicing, the destruction of the messenger RNA, theprevention of the post-translational modifications of the protein, thedestruction of the protein, or the inhibition of the normal function ofthe protein.

For local administration to abnormally proliferating cells,polynucleotides of the present invention may be administered by anymethod known to those of skill in the art including, but not limited totransfection, electroporation, microinjection of cells, or in vehiclessuch as liposomes, lipofectin, or as naked polynucleotides, or any othermethod described throughout the specification. The polynucleotide of thepresent invention may be delivered by known gene delivery systems suchas, but not limited to, retroviral vectors (Gilboa, J. Virology 44:845(1982); Hocke, Nature 320:275 (1986); Wilson, et al., Proc. Natl. Acad.Sci. U.S.A. 85:3014), vaccinia virus system (Chakrabarty et al., Mol.Cell Biol. 5:3403 (1985) or other efficient DNA delivery systems (Yateset al., Nature 313:812 (1985)) known to those skilled in the art. Thesereferences are exemplary only and are hereby incorporated by reference.In order to specifically deliver or transfect cells which are abnormallyproliferating and spare non-dividing cells, it is preferable to utilizea retrovirus, or adenoviral (as described in the art and elsewhereherein) delivery system known to those of skill in the art. Since hostDNA replication is required for retroviral DNA to integrate and theretrovirus will be unable to self replicate due to the lack of theretrovirus genes needed for its life cycle. Utilizing such a retroviraldelivery system for polynucleotides of the present invention will targetsaid gene and constructs to abnormally proliferating cells and willspare the non-dividing normal cells.

The polynucleotides of the present invention may be delivered directlyto cell proliferative disorder/disease sites in internal organs, bodycavities and the like by use of imaging devices used to guide aninjecting needle directly to the disease site. The polynucleotides ofthe present invention may also be administered to disease sites at thetime of surgical intervention.

By “cell proliferative disease” is meant any human or animal disease ordisorder, affecting any one or any combination of organs, cavities, orbody parts, which is characterized by single or multiple local abnormalproliferations of cells, groups of cells, or tissues, whether benign ormalignant.

Any amount of the polynucleotides of the present invention may beadministered as long as it has a biologically inhibiting effect on theproliferation of the treated cells. Moreover, it is possible toadminister more than one of the polynucleotide of the present inventionsimultaneously to the same site. By “biologically inhibiting” is meantpartial or total growth inhibition as well as decreases in the rate ofproliferation or growth of the cells. The biologically inhibitory dosemay be determined by assessing the effects of the polynucleotides of thepresent invention on target malignant or abnormally proliferating cellgrowth in tissue culture, tumor growth in animals and cell cultures, orany other method known to one of ordinary skill in the art.

The present invention is further directed to antibody-based therapieswhich involve administering of anti-polypeptides and anti-polynucleotideantibodies to a mammalian, preferably human, patient for treating one ormore of the described disorders. Methods for producing anti-polypeptidesand anti-polynucleotide antibodies polyclonal and monoclonal antibodiesare described in detail elsewhere herein. Such antibodies may beprovided in pharmaceutically acceptable compositions as known in the artor as described herein.

A summary of the ways in which the antibodies of the present inventionmay be used therapeutically includes binding polynucleotides orpolypeptides of the present invention locally or systemically in thebody or by direct cytotoxicity of the antibody, e.g. as mediated bycomplement (CDC) or by effector cells (ADCC). Some of these approachesare described in more detail below. Armed with the teachings providedherein, one of ordinary skill in the art will know how to use theantibodies of the present invention for diagnostic, monitoring ortherapeutic purposes without undue experimentation.

In particular, the antibodies, fragments and derivatives of the presentinvention are useful for treating a subject having or developing cellproliferative and/or differentiation disorders as described herein. Suchtreatment comprises administering a single or multiple doses of theantibody, or a fragment, derivative, or a conjugate thereof.

The antibodies of this invention may be advantageously utilized incombination with other monoclonal or chimeric antibodies, or withlymphokines or hematopoietic growth factors, for example., which serveto increase the number or activity of effector cells which interact withthe antibodies.

It is preferred to use high affinity and/or potent in vivo inhibitingand/or neutralizing antibodies against polypeptides or polynucleotidesof the present invention, fragments or regions thereof, for bothimmunoassays directed to and therapy of disorders related topolynucleotides or polypeptides, including fragements thereof, of thepresent invention. Such antibodies, fragments, or regions, willpreferably have an affinity for polynucleotides or polypeptides,including fragements thereof. Preferred binding affinities include thosewith a dissociation constant or Kd less than 5×10⁻⁶ M, 10⁻⁶M, 5×10⁻⁷M,10⁻⁷M, 5×10⁻⁸M, 10⁻⁸M, 5×10⁻⁹M, 10⁻⁹M, 5×10⁻¹⁰ M, 10⁻¹⁰ M, 5×10⁻¹¹ M,10⁻¹¹ M, 5×10⁻¹²M, 10⁻¹²M, 5×10⁻¹³M, 10⁻¹³M, 5×10⁻¹⁴M, 10⁻¹⁴M, 5×10⁻¹⁵M,and 10⁻¹⁵M.

Moreover, polypeptides of the present invention are useful in inhibitingthe angiogenesis of proliferative cells or tissues, either alone, as aprotein fusion, or in combination with other polypeptides directly orindirectly, as described elsewhere herein. In a most preferredembodiment, said anti-angiogenesis effect may be achieved indirectly,for example, through the inhibition of hematopoietic, tumor-specificcells, such as tumor-associated macrophages (See Joseph I B, et al. JNatl Cancer Inst, 90(21):1648-53 (1998), which is hereby incorporated byreference). Antibodies directed to polypeptides or polynucleotides ofthe present invention may also result in inhibition of angiogenesisdirectly, or indirectly (See Witte L, et al., Cancer Metastasis Rev.17(2):155-61 (1998), which is hereby incorporated by reference)).

Polypeptides, including protein fusions, of the present invention, orfragments thereof may be useful in inhibiting proliferative cells ortissues through the induction of apoptosis. Said polypeptides may acteither directly, or indirectly to induce apoptosis of proliferativecells and tissues, for example in the activation of a death-domainreceptor, such as tumor necrosis factor (TNF) receptor-1, CD95(Fas/APO-1), TNF-receptor-related apoptosis-mediated protein (TRAMP) andTNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2 (SeeSchulze-Osthoff K, et. al., Eur J Biochem 254(3):439-59 (1998), which ishereby incorporated by reference). Moreover, in another preferredembodiment of the present invention, said polypeptides may induceapoptosis through other mechanisms, such as in the activation of otherproteins which will activate apoptosis, or through stimulating theexpression of said proteins, either alone or in combination with smallmolecule drugs or adjuvants, such as apoptonin, galectins, thioredoxins,anti-inflammatory proteins (See for example, Mutat Res 400(1-2):447-55(1998), Med Hypotheses.50(5):423-33 (1998), Chem Biol Interact. April24; 111-112:23-34 (1998), J Mol Med.76(6):402-12 (1998), Int J TissueReact; 20(1):3-15 (1998), which are all hereby incorporated byreference).

Polypeptides, including protein fusions to, or fragments thereof, of thepresent invention are useful in inhibiting the metastasis ofproliferative cells or tissues. Inhibition may occur as a direct resultof administering polypeptides, or antibodies directed to saidpolypeptides as described elsewere herein, or indirectly, such asactivating the expression of proteins known to inhibit metastasis, forexample alpha 4 integrins, (See, e.g., Curr Top Microbiol Immunol1998;231:125-41, which is hereby incorporated by reference). Suchtherapeutic affects of the present invention may be achieved eitheralone, or in combination with small molecule drugs or adjuvants.

In another embodiment, the invention provides a method of deliveringcompositions containing the polypeptides of the invention (e.g.,compositions containing polypeptides or polypeptide antibodes associatedwith heterologous polypeptides, heterologous nucleic acids, toxins, orprodrugs) to targeted cells expressing the polypeptide of the presentinvention. Polypeptides or polypeptide antibodes of the invention may beassociated with with heterologous polypeptides, heterologous nucleicacids, toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/orcovalent interactions.

Polypeptides, protein fusions to, or fragments thereof, of the presentinvention are useful in enhancing the immunogenicity and/or antigenicityof proliferating cells or tissues, either directly, such as would occurif the polypeptides of the present invention ‘vaccinated’ the immuneresponse to respond to proliferative antigens and immunogens, orindirectly, such as in activating the expression of proteins known toenhance the immune response (e.g. chemokines), to said antigens andimmunogens.

Renal Disorders

Polynucleotides, polypeptides, antibodies, and/or agonists orantagonists of the present invention, may be used to treat, prevent,diagnose, and/or prognose disorders of the renal system. Renal disorderswhich can be diagnosed, prognosed, prevented, and/or treated withcompositions of the invention include, but are not limited to, kidneyfailure, nephritis, blood vessel disorders of kidney, metabolic andcongenital kidney disorders, urinary disorders of the kidney, autoimmunedisorders, sclerosis and necrosis, electrolyte imbalance, and kidneycancers.

Kidney diseases which can be diagnosed, prognosed, prevented, and/ortreated with compositions of the invention include, but are not limitedto, acute kidney failure, chronic kidney failure, atheroembolic renalfailure, end-stage renal disease, inflammatory diseases of the kidney(e.g., acute glomerulonephritis, postinfectious glomerulonephritis,rapidly progressive glomerulonephritis, nephrotic syndrome, membranousglomerulonephritis, familial nephrotic syndrome, membranoproliferativeglomerulonephritis I and II, mesangial proliferative glomerulonephritis,chronic glomerulonephritis, acute tubulointerstitial nephritis, chronictubulointerstitial nephritis, acute post-streptococcalglomerulonephritis (PSGN), pyelonephritis, lupus nephritis, chronicnephritis, interstitial nephritis, and post-streptococcalglomerulonephritis), blood vessel disorders of the kidneys (e.g., kidneyinfarction, atheroembolic kidney disease, cortical necrosis, malignantnephrosclerosis, renal vein thrombosis, renal underperfusion, renalretinopathy, renal ischemia-reperfusion, renal artery embolism, andrenal artery stenosis), and kidney disorders resulting form urinarytract disease (e.g., pyelonephritis, hydronephrosis, urolithiasis (renallithiasis, nephrolithiasis), reflux nephropathy, urinary tractinfections, urinary retention, and acute or chronic unilateralobstructive uropathy.)

In addition, compositions of the invention can be used to diagnose,prognose, prevent, and/or treat metabolic and congenital disorders ofthe kidney (e.g., uremia, renal amyloidosis, renal osteodystrophy, renaltubular acidosis, renal glycosuria, nephrogenic diabetes insipidus,cystinuria, Fanconi's syndrome, renal fibrocystic osteosis (renalrickets), Hartnup disease, Bartter's syndrome, Liddle's syndrome,polycystic kidney disease, medullary cystic disease, medullary spongekidney, Alport's syndrome, nail-patella syndrome, congenital nephroticsyndrome, CRUSH syndrome, horseshoe kidney, diabetic nephropathy,nephrogenic diabetes insipidus, analgesic nephropathy, kidney stones,and membranous nephropathy), and autoimmune disorders of the kidney(e.g., systemic lupus erythematosus (SLE), Goodpasture syndrome, IgAnephropathy, and IgM mesangial proliferative glomerulonephritis).

Compositions of the invention can also be used to diagnose, prognose,prevent, and/or treat sclerotic or necrotic disorders of the kidney(e.g., glomerulosclerosis, diabetic nephropathy, focal segmentalglomerulosclerosis (FSGS), necrotizing glomerulonephritis, and renalpapillary necrosis), cancers of the kidney (e.g., nephroma,hypemephroma, nephroblastoma, renal cell cancer, transitional cellcancer, renal adenocarcinoma, squamous cell cancer, and Wilm's tumor),and electrolyte imbalances (e.g., nephrocalcinosis, pyuria, edema,hydronephritis, proteinuria, hyponatremia, hypernatremia, hypokalemia,hyperkalemia, hypocalcemia, hypercalcemia, hypophosphatemia, andhyperphosphatemia).

Polypeptides may be administered using any method known in the art,including, but not limited to, direct needle injection at the deliverysite, intravenous injection, topical administration, catheter infusion,biolistic injectors, particle accelerators, gelfoam sponge depots, othercommercially available depot materials, osmotic pumps, oral orsuppositorial solid pharmaceutical formulations, decanting or topicalapplications during surgery, aerosol delivery. Such methods are known inthe art. Polypeptides may be administered as part of a Therapeutic,described in more detail below. Methods of delivering polynucleotidesare described in more detail herein.

Cardiovascular Disorders

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention, may be used to treat, prevent, diagnose, and/orprognose cardiovascular disorders, including, but not limited to,peripheral artery disease, such as limb ischemia.

Cardiovascular disorders include, but are not limited to, cardiovascularabnormalities, such as arterio-arterial fistula, arteriovenous fistula,cerebral arteriovenous malformations, congenital heart defects,pulmonary atresia, and Scimitar Syndrome. Congenital heart defectsinclude, but are not limited to, aortic coarctation, cor triatriatum,coronary vessel anomalies, crisscross heart, dextrocardia, patent ductusarteriosus, Ebstein's anomaly, Eisenmenger complex, hypoplastic leftheart syndrome, levocardia, tetralogy of fallot, transposition of greatvessels, double outlet right ventricle, tricuspid atresia, persistenttruncus arteriosus, and heart septal defects, such as aortopulmonaryseptal defect, endocardial cushion defects, Lutembacher's Syndrome,trilogy of Fallot, ventricular heart septal defects.

Cardiovascular disorders also include, but are not limited to, heartdisease, such as arrhythmias, carcinoid heart disease, high cardiacoutput, low cardiac output, cardiac tamponade, endocarditis (includingbacterial), heart aneurysm, cardiac arrest, congestive heart failure,congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, hearthypertrophy, congestive cardiomyopathy, left ventricular hypertrophy,right ventricular hypertrophy, post-infarction heart rupture,ventricular septal rupture, heart valve diseases, myocardial diseases,myocardial ischemia, pericardial effusion, pericarditis (includingconstrictive and tuberculous), pneumopericardium, postpericardiotomysyndrome, pulmonary heart disease, rheumatic heart disease, ventriculardysfunction, hyperemia, cardiovascular pregnancy complications, ScimitarSyndrome, cardiovascular syphilis, and cardiovascular tuberculosis.

Arrhythmias include, but are not limited to, sinus arrhythmia, atrialfibrillation, atrial flutter, bradycardia, extrasystole, Adams-StokesSyndrome, bundle-branch block, sinoatrial block, long QT syndrome,parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitationsyndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome,tachycardias, and ventricular fibrillation. Tachycardias includeparoxysmal tachycardia, supraventricular tachycardia, acceleratedidioventricular rhythm, atrioventricular nodal reentry tachycardia,ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrialnodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, andventricular tachycardia.

Heart valve diseases include, but are not limited to, aortic valveinsufficiency, aortic valve stenosis, hear murmurs, aortic valveprolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valveinsufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valveinsufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspidvalve insufficiency, and tricuspid valve stenosis.

Myocardial diseases include, but are not limited to, alcoholiccardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy,aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictivecardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis,endomyocardial fibrosis, Kearns Syndrome, myocardial reperfusion injury,and myocarditis.

Myocardial ischemias include, but are not limited to, coronary disease,such as angina pectoris, coronary aneurysm, coronary arteriosclerosis,coronary thrombosis, coronary vasospasm, myocardial infarction andmyocardial stunning.

Cardiovascular diseases also include vascular diseases such asaneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis,Hippel-Lindau Disease, Klippel-Trenaunay-Weber Syndrome, Sturge-WeberSyndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis,aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis,enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabeticangiopathies, diabetic retinopathy, embolisms, thrombosis,erythromelalgia, hemorrhoids, hepatic veno-occlusive disease,hypertension, hypotension, ischemia, peripheral vascular diseases,phlebitis, pulmonary veno-occlusive disease, Raynaud's disease, CRESTsyndrome, retinal vein occlusion, Scimitar syndrome, superior vena cavasyndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagictelangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis,and venous insufficiency.

Aneurysms include, but are not limited to, dissecting aneurysms, falseaneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms,cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliacaneurysms.

Arterial occlusive diseases include, but are not limited to,arteriosclerosis, intermittent claudication, carotid stenosis,fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoyadisease, renal artery obstruction, retinal artery occlusion, andthromboangiitis obliterans.

Cerebrovascular disorders include, but are not limited to, carotidartery diseases, cerebral amyloid angiopathy, cerebral aneurysm,cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenousmalformation, cerebral artery diseases, cerebral embolism andthrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg'ssyndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma,subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia(including transient), subclavian steal syndrome, periventricularleukomalacia, vascular headache, cluster headache, migraine, andvertebrobasilar insufficiency.

Embolisms include, but are not limited to, air embolisms, amniotic fluidembolisms, cholesterol embolisms, blue toe syndrome, fat embolisms,pulmonary embolisms, and thromoboembolisms. Thrombosis include, but arenot limited to, coronary thrombosis, hepatic vein thrombosis, retinalvein occlusion, carotid artery thrombosis, sinus thrombosis,Wallenberg's syndrome, and thrombophlebitis.

Ischemic disorders include, but are not limited to, cerebral ischemia,ischemic colitis, compartment syndromes, anterior compartment syndrome,myocardial ischemia, reperfusion injuries, and peripheral limb ischemia.Vasculitis includes, but is not limited to, aortitis, arteritis,Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph nodesyndrome, thromboangiitis obliterans, hypersensitivity vasculitis,Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener'sgranulomatosis.

Polypeptides may be administered using any method known in the art,including, but not limited to, direct needle injection at the deliverysite, intravenous injection, topical administration, catheter infusion,biolistic injectors, particle accelerators, gelfoam sponge depots, othercommercially available depot materials, osmotic pumps, oral orsuppositorial solid pharmaceutical formulations, decanting or topicalapplications during surgery, aerosol delivery. Such methods are known inthe art. Polypeptides may be administered as part of a Therapeutic,described in more detail below. Methods of delivering polynucleotidesare described in more detail herein.

Respiratory Disorders

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention may be used to treat, prevent, diagnose, and/orprognose diseases and/or disorders of the respiratory system.

Diseases and disorders of the respiratory system include, but are notlimited to, nasal vestibulitis, nonallergic rhinitis (e.g., acuterhinitis, chronic rhinitis, atrophic rhinitis, vasomotor rhinitis),nasal polyps, and sinusitis, juvenile angiofibromas, cancer of the noseand juvenile papillomas, vocal cord polyps, nodules (singer's nodules),contact ulcers, vocal cord paralysis, laryngoceles, pharyngitis (e.g.,viral and bacterial), tonsillitis, tonsillar cellulitis, parapharyngealabscess, laryngitis, laryngoceles, and throat cancers (e.g., cancer ofthe nasopharynx, tonsil cancer, larynx cancer), lung cancer (e.g.,squamous cell carcinoma, small cell (oat cell) carcinoma, large cellcarcinoma, and adenocarcinoma), allergic disorders (eosinophilicpneumonia, hypersensitivity pneumonitis (e.g., extrinsic allergicalveolitis, allergic interstitial pneumonitis, organic dustpneumoconiosis, allergic bronchopulmonary aspergillosis, asthma,Wegener's granulomatosis (granulomatous vasculitis), Goodpasture'ssyndrome)), pneumonia (e.g., bacterial pneumonia (e.g., Streptococcuspneumoniae (pneumoncoccal pneumonia), Staphylococcusaureus(staphylococcal pneumonia), Gram-negative bacterial pneumonia(caused by, e.g., Klebsiella and Pseudomas spp.), Mycoplasma pneumoniaepneumonia, Hemophilus influenzae pneumonia, Legionella pneumophila(Legionnaires' disease), and Chlamydia psittaci (Psittacosis)), andviral pneumonia (e.g., influenza, chickenpox (varicella).

Additional diseases and disorders of the respiratory system include, butare not limited to bronchiolitis, polio (poliomyelitis), croup,respiratory syncytial viral infection, mumps, erythema infectiosum(fifth disease), roseola infantum, progressive rubella panencephalitis,german measles, and subacute sclerosing panencephalitis), fungalpneumonia (e.g., Histoplasmosis, Coccidioidomycosis, Blastomycosis,ftungal infections in people with severely suppressed immune systems(e.g., cryptococcosis, caused by Cryptococcus neoformans; aspergillosis,caused by Aspergillus spp.; candidiasis, caused by Candida; andmucormycosis)), Pneumocystis carinii (pneumocystis pneumonia), atypicalpneumonias (e.g., Mycoplasma and Chlamydia spp.), opportunisticinfection pneumonia, nosocomial pneumonia, chemical pneumonitis, andaspiration pneumonia, pleural disorders (e.g., pleurisy, pleuraleffusion, and pneumothorax (e.g., simple spontaneous pneumothorax,complicated spontaneous pneumothorax, tension pneumothorax)),obstructive airway diseases (e.g., asthma, chronic obstructive pulmonarydisease (COPD), emphysema, chronic or acute bronchitis), occupationallung diseases (e.g., silicosis, black lung (coal workers'pneumoconiosis), asbestosis, berylliosis, occupational asthsma,byssinosis, and benign pneumoconioses), Infiltrative Lung Disease (e.g.,pulmonary fibrosis (e.g., fibrosing alveolitis, usual interstitialpneumonia), idiopathic pulmonary fibrosis, desquamative interstitialpneumonia, lymphoid interstitial pneumonia, histiocytosis X (e.g.,Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilicgranuloma), idiopathic pulmonary hemosiderosis, sarcoidosis andpulmonary alveolar proteinosis), Acute respiratory distress syndrome(also called, e.g., adult respiratory distress syndrome), edema,pulmonary embolism, bronchitis (e.g., viral, bacterial), bronchiectasis,atelectasis, lung abscess (caused by, e.g., Staphylococcus aureus orLegionella pneumophila), and cystic fibrosis.

Anti-Angiogenesis Activity

The naturally occurring balance between endogenous stimulators andinhibitors of angiogenesis is one in which inhibitory influencespredominate. Rastinejad et al., Cell 56:345-355 (1989). In those rareinstances in which neovascularization occurs under normal physiologicalconditions, such as wound healing, organ regeneration, embryonicdevelopment, and female reproductive processes, angiogenesis isstringently regulated and spatially and temporally delimited. Underconditions of pathological angiogenesis such as that characterizingsolid tumor growth, these regulatory controls fail. Unregulatedangiogenesis becomes pathologic and sustains progression of manyneoplastic and non-neoplastic diseases. A number of serious diseases aredominated by abnormal neovascularization including solid tumor growthand metastases, arthritis, some types of eye disorders, and psoriasis.See, e.g., reviews by Moses et al., Biotech. 9:630-634 (1991); Folkmanet al., N. Engl. J. Med., 333:1757-1763 (1995); Auerbach et al., JMicrovasc. Res. 29:401-411 (1985); Folkman, Advances in Cancer Research,eds. Klein and Weinhouse, Academic Press, New York, pp. 175-203 (1985);Patz, Am. J. Opthalmol. 94:715-743 (1982); and Folkman et al., Science221:719-725 (1983). In a number of pathological conditions, the processof angiogenesis contributes to the disease state. For example,significant data have accumulated which suggest that the growth of solidtumors is dependent on angiogenesis. Folkman and Klagsbrun, Science235:442-447 (1987).

The present invention provides for treatment of diseases or disordersassociated with neovascularization by administration of thepolynucleotides and/or polypeptides of the invention, as well asagonists or antagonists of the present invention. Malignant andmetastatic conditions which can be treated with the polynucleotides andpolypeptides, or agonists or antagonists of the invention include, butare not limited to, malignancies, solid tumors, and cancers describedherein and otherwise known in the art (for a review of such disorders,see Fishman et al., Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia(1985)). Thus, the present invention provides a method of treating anangiogenesis-related disease and/or disorder, comprising administeringto an individual in need thereof a therapeutically effective amount of apolynucleotide, polypeptide, antagonist and/or agonist of the invention.For example, polynucleotides, polypeptides, antagonists and/or agonistsmay be utilized in a variety of additional methods in order totherapeutically treat a cancer or tumor. Cancers which may be treatedwith polynucleotides, polypeptides, antagonists and/or agonists include,but are not limited to solid tumors, including prostate, lung, breast,ovarian, stomach, pancreas, larynx, esophagus, testes, liver, parotid,biliary tract, colon, rectum, cervix, uterus, endometrium, kidney,bladder, thyroid cancer; primary tumors and metastases; melanomas;glioblastoma; Kaposi's sarcoma; leiomyosarcoma; non-small cell lungcancer; colorectal cancer; advanced malignancies; and blood born tumorssuch as leukemias. For example, polynucleotides, polypeptides,antagonists and/or agonists may be delivered topically, in order totreat cancers such as skin cancer, head and neck tumors, breast tumors,and Kaposi's sarcoma.

Within yet other aspects, polynucleotides, polypeptides, antagonistsand/or agonists may be utilized to treat superficial forms of bladdercancer by, for example, intravesical administration. Polynucleotides,polypeptides, antagonists and/or agonists may be delivered directly intothe tumor, or near, the tumor site, via injection or a catheter. Ofcourse, as the artisan of ordinary skill will appreciate, theappropriate mode of administration will vary according to the cancer tobe treated. Other modes of delivery are discussed herein.

Polynucleotides, polypeptides, antagonists and/or agonists may be usefulin treating other disorders, besides cancers, which involveangiogenesis. These disorders include, but are not limited to: benigntumors, for example hemangiomas, acoustic neuromas, neurofibromas,trachomas, and pyogenic granulomas; artheroscleric plaques; ocularangiogenic diseases, for example, diabetic retinopathy, retinopathy ofprematurity, macular degeneration, corneal graft rejection, neovascularglaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, uvietis andPterygia (abnormal blood vessel growth) of the eye; rheumatoidarthritis; psoriasis; delayed wound healing; endometriosis;vasculogenesis; granulations; hypertrophic scars (keloids); nonunionfractures; scleroderma; trachoma; vascular adhesions; myocardialangiogenesis; coronary collaterals; cerebral collaterals; arteriovenousmalformations; ischemic limb angiogenesis; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; angiofibroma;fibromuscular dysplasia; wound granulation; Crohn's disease; andatherosclerosis.

For example, within one aspect of the present invention methods areprovided for treating hypertrophic scars and keloids, comprising thestep of administering a polynucleotide, polypeptide, antagonist and/oragonist of the invention to a hypertrophic scar or keloid.

Within one embodiment of the present invention polynucleotides,polypeptides, antagonists and/or agonists of the invention are directlyinjected into a hypertrophic scar or keloid, in order to prevent theprogression of these lesions. This therapy is of particular value in theprophylactic treatment of conditions which are known to result in thedevelopment of hypertrophic scars and keloids (e.g., burns), and ispreferably initiated after the proliferative phase has had time toprogress (approximately 14 days after the initial injury), but beforehypertrophic scar or keloid development. As noted above, the presentinvention also provides methods for treating neovascular diseases of theeye, including for example, corneal neovascularization, neovascularglaucoma, proliferative diabetic retinopathy, retrolental fibroplasiaand macular degeneration.

Moreover, Ocular disorders associated with neovascularization which canbe treated with the polynucleotides and polypeptides of the presentinvention (including agonists and/or antagonists) include, but are notlimited to: neovascular glaucoma, diabetic retinopathy, retinoblastoma,retrolental fibroplasia, uveitis, retinopathy of prematurity maculardegeneration, corneal graft neovascularization, as well as other eyeinflammatory diseases, ocular tumors and diseases associated withchoroidal or iris neovascularization. See, e.g., reviews by Waltman etal., Am. J Ophthal. 85:704-710 (1978) and Gartner et al., Surv. Ophthal.22:291-312 (1978).

Thus, within one aspect of the present invention methods are providedfor treating neovascular diseases of the eye such as cornealneovascularization (including corneal graft neovascularization),comprising the step of administering to a patient a therapeuticallyeffective amount of a compound (as described above) to the cornea, suchthat the formation of blood vessels is inhibited. Briefly, the cornea isa tissue which normally lacks blood vessels. In certain pathologicalconditions however, capillaries may extend into the cornea from thepericorneal vascular plexus of the limbus. When the cornea becomesvascularized, it also becomes clouded, resulting in a decline in thepatient's visual acuity. Visual loss may become complete if the corneacompletely opacitates. A wide variety of disorders can result in cornealneovascularization, including for example, corneal infections (e.g.,trachoma, herpes simplex keratitis, leishmaniasis and onchocerciasis),immunological processes (e.g., graft rejection and Stevens-Johnson'ssyndrome), alkali burns, trauma, inflammation (of any cause), toxic andnutritional deficiency states, and as a complication of wearing contactlenses.

Within particularly preferred embodiments of the invention, may beprepared for topical administration in saline (combined with any of thepreservatives and antimicrobial agents commonly used in ocularpreparations), and administered in eyedrop form. The solution orsuspension may be prepared in its pure form and administered severaltimes daily. Alternatively, anti-angiogenic compositions, prepared asdescribed above, may also be administered directly to the cornea. Withinpreferred embodiments, the anti-angiogenic composition is prepared witha muco-adhesive polymer which binds to cornea. Within furtherembodiments, the anti-angiogenic factors or anti-angiogenic compositionsmay be utilized as an adjunct to conventional steroid therapy. Topicaltherapy may also be useful prophylactically in corneal lesions which areknown to have a high probability of inducing an angiogenic response(such as chemical burns). In these instances the treatment, likely incombination with steroids, may be instituted immediately to help preventsubsequent complications.

Within other embodiments, the compounds described above may be injecteddirectly into the corneal stroma by an ophthalmologist under microscopicguidance. The preferred site of injection may vary with the morphologyof the individual lesion, but the goal of the administration would be toplace the composition at the advancing front of the vasculature (i.e.,interspersed between the blood vessels and the normal cornea). In mostcases this would involve perilimbic corneal injection to “protect” thecornea from the advancing blood vessels. This method may also beutilized shortly after a corneal insult in order to prophylacticallyprevent corneal neovascularization. In this situation the material couldbe injected in the perilimbic cornea interspersed between the corneallesion and its undesired potential limbic blood supply. Such methods mayalso be utilized in a similar fashion to prevent capillary invasion oftransplanted corneas. In a sustained-release form injections might onlybe required 2-3 times per year. A steroid could also be added to theinjection solution to reduce inflammation resulting from the injectionitself.

Within another aspect of the present invention, methods are provided fortreating neovascular glaucoma, comprising the step of administering to apatient a therapeutically effective amount of a polynucleotide,polypeptide, antagonist and/or agonist to the eye, such that theformation of blood vessels is inhibited. In one embodiment, the compoundmay be administered topically to the eye in order to treat early formsof neovascular glaucoma. Within other embodiments, the compound may beimplanted by injection into the region of the anterior chamber angle.Within other embodiments, the compound may also be placed in anylocation such that the compound is continuously released into theaqueous humor. Within another aspect of the present invention, methodsare provided for treating proliferative diabetic retinopathy, comprisingthe step of administering to a patient a therapeutically effectiveamount of a polynucleotide, polypeptide, antagonist and/or agonist tothe eyes, such that the formation of blood vessels is inhibited.

Within particularly preferred embodiments of the invention,proliferative diabetic retinopathy may be treated by injection into theaqueous humor or the vitreous, in order to increase the localconcentration of the polynucleotide, polypeptide, antagonist and/oragonist in the retina. Preferably, this treatment should be initiatedprior to the acquisition of severe disease requiring photocoagulation.

Within another aspect of the present invention, methods are provided fortreating retrolental fibroplasia, comprising the step of administeringto a patient a therapeutically effective amount of a polynucleotide,polypeptide, antagonist and/or agonist to the eye, such that theformation of blood vessels is inhibited. The compound may beadministered topically, via intravitreous injection and/or viaintraocular implants.

Additionally, disorders which can be treated with the polynucleotides,polypeptides, agonists and/or agonists include, but are not limited to,hemangioma, arthritis, psoriasis, angiofibroma, atherosclerotic plaques,delayed wound healing, granulations, hemophilic joints, hypertrophicscars, nonunion fractures, Osler-Weber syndrome, pyogenic granuloma,scleroderma, trachoma, and vascular adhesions.

Moreover, disorders and/or states, which can be treated, prevented,diagnosed, and/or prognosed with the the polynucleotides, polypeptides,agonists and/or agonists of the invention include, but are not limitedto, solid tumors, blood born tumors such as leukemias, tumor metastasis,Kaposi's sarcoma, benign tumors, for example hemangiomas, acousticneuromas, neurofibromas, trachomas, and pyogenic granulomas, rheumatoidarthritis, psoriasis, ocular angiogenic diseases, for example, diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, and uvietis, delayed wound healing,endometriosis, vascluogenesis, granulations, hypertrophic scars(keloids), nonunion fractures, scleroderma, trachoma, vascularadhesions, myocardial angiogenesis, coronary collaterals, cerebralcollaterals, arteriovenous malformations, ischemic limb angiogenesis,Osler-Webber Syndrome, plaque neovascularization, telangiectasia,hemophiliac joints, angiofibroma fibromuscular dysplasia, woundgranulation, Crohn's disease, atherosclerosis, birth control agent bypreventing vascularization required for embryo implantation controllingmenstruation, diseases that have angiogenesis as a pathologicconsequence such as cat scratch disease (Rochele minalia quintosa),ulcers (Helicobacter pylori), Bartonellosis and bacillary angiomatosis.

In one aspect of the birth control method, an amount of the compoundsufficient to block embryo implantation is administered before or afterintercourse and fertilization have occurred, thus providing an effectivemethod of birth control, possibly a “morning after” method.Polynucleotides, polypeptides, agonists and/or agonists may also be usedin controlling menstruation or administered as either a peritoneallavage fluid or for peritoneal implantation in the treatment ofendometriosis.

Polynucleotides, polypeptides, agonists and/or agonists of the presentinvention may be incorporated into surgical sutures in order to preventstitch granulomas.

Polynucleotides, polypeptides, agonists and/or agonists may be utilizedin a wide variety of surgical procedures. For example, within one aspectof the present invention a compositions (in the form of, for example, aspray or film) may be utilized to coat or spray an area prior to removalof a tumor, in order to isolate normal surrounding tissues frommalignant tissue, and/or to prevent the spread of disease to surroundingtissues. Within other aspects of the present invention, compositions(e.g., in the form of a spray) may be delivered via endoscopicprocedures in order to coat tumors, or inhibit angiogenesis in a desiredlocale. Within yet other aspects of the present invention, surgicalmeshes which have been coated with anti-angiogenic compositions of thepresent invention may be utilized in any procedure wherein a surgicalmesh might be utilized. For example, within one embodiment of theinvention a surgical mesh laden with an anti-angiogenic composition maybe utilized during abdominal cancer resection surgery (e.g., subsequentto colon resection) in order to provide support to the structure, and torelease an amount of the anti-angiogenic factor.

Within further aspects of the present invention, methods are providedfor treating tumor excision sites, comprising administering apolynucleotide, polypeptide, agonist and/or agonist to the resectionmargins of a tumor subsequent to excision, such that the localrecurrence of cancer and the formation of new blood vessels at the siteis inhibited. Within one embodiment of the invention, theanti-angiogenic compound is administered directly to the tumor excisionsite (e.g., applied by swabbing, brushing or otherwise coating theresection margins of the tumor with the anti-angiogenic compound).Alternatively, the anti-angiogenic compounds may be incorporated intoknown surgical pastes prior to administration. Within particularlypreferred embodiments of the invention, the anti-angiogenic compoundsare applied after hepatic resections for malignancy, and afterneurosurgical operations.

Within one aspect of the present invention, polynucleotides,polypeptides, agonists and/or agonists may be administered to theresection margin of a wide variety of tumors, including for example,breast, colon, brain and hepatic tumors. For example, within oneembodiment of the invention, anti-angiogenic compounds may beadministered to the site of a neurological tumor subsequent to excision,such that the formation of new blood vessels at the site are inhibited.

The polynucleotides, polypeptides, agonists and/or agonists of thepresent invention may also be administered along with otheranti-angiogenic factors. Representative examples of otheranti-angiogenic factors include: Anti-Invasive Factor, retinoic acid andderivatives thereof, paclitaxel, Suramin, Tissue Inhibitor ofMetalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2,Plasminogen Activator Inhibitor-1, Plasminogen Activator Inhibitor-2,and various forms of the lighter “d group” transition metals.

Lighter “d group” transition metals include, for example, vanadium,molybdenum, tungsten, titanium, niobium, and tantalum species. Suchtransition metal species may form transition metal complexes. Suitablecomplexes of the above-mentioned transition metal species include oxotransition metal complexes.

Representative examples of vanadium complexes include oxo vanadiumcomplexes such as vanadate and vanadyl complexes. Suitable vanadatecomplexes include metavanadate and orthovanadate complexes such as, forexample, ammonium metavanadate, sodium metavanadate, and sodiumorthovanadate. Suitable vanadyl complexes include, for example, vanadylacetylacetonate and vanadyl sulfate including vanadyl sulfate hydratessuch as vanadyl sulfate mono- and trihydrates.

Representative examples of tungsten and molybdenum complexes alsoinclude oxo complexes. Suitable oxo tungsten complexes include tungstateand tungsten oxide complexes. Suitable tungstate complexes includeammonium tungstate, calcium tungstate, sodium tungstate dihydrate, andtungstic acid. Suitable tungsten oxides include tungsten (IV) oxide andtungsten (VI) oxide. Suitable oxo molybdenum complexes includemolybdate, molybdenum oxide, and molybdenyl complexes. Suitablemolybdate complexes include ammonium molybdate and its hydrates, sodiummolybdate and its hydrates, and potassium molybdate and its hydrates.Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum(VI) oxide, and molybdic acid. Suitable molybdenyl complexes include,for example, molybdenyl acetylacetonate. Other suitable tungsten andmolybdenum complexes include hydroxo derivatives derived from, forexample, glycerol, tartaric acid, and sugars.

A wide variety of other anti-angiogenic factors may also be utilizedwithin the context of the present invention. Representative examplesinclude platelet factor 4; protamine sulphate; sulphated chitinderivatives (prepared from queen crab shells), (Murata et al., CancerRes. 51:22-26, 1991); Sulphated Polysaccharide Peptidoglycan Complex(SP-PG) (the function of this compound may be enhanced by the presenceof steroids such as estrogen, and tamoxifen citrate); Staurosporine;modulators of matrix metabolism, including for example, proline analogs,cishydroxyproline, d,L-3,4-dehydroproline, Thiaproline,alpha,alpha-dipyridyl, aminopropionitrile fumarate;4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone;Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J.Bio. Chem. 267:17321-17326, 1992); Chymostatin (Tomkinson et al.,Biochem J. 286:475-480, 1992); Cyclodextrin Tetradecasulfate;Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557,1990); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin.Invest. 79:1440-1446, 1987); anticollagenase-serum; alpha2-antiplasmin(Holmes et al., J. Biol. Chem. 262(4):1659-1664, 1987); Bisantrene(National Cancer Institute); Lobenzarit disodium(N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”;Takeuchi et al., Agents Actions 36:312-316, 1992); Thalidomide;Angostatic steroid; AGM-1470; carboxynaminolmidazole; andmetalloproteinase inhibitors such as BB94.

Diseases at the Cellular Level

Diseases associated with increased cell survival or the inhibition ofapoptosis that could be treated, prevented, diagnosed, and/or prognosedusing polynucleotides or polypeptides, as well as antagonists oragonists of the present invention, include cancers (such as follicularlymphomas, carcinomas with p53 mutations, and hormone-dependent tumors,including, but not limited to colon cancer, cardiac tumors, pancreaticcancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinalcancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma,lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma,chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi'ssarcoma and ovarian cancer); autoimmune disorders (such as, multiplesclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliarycirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemiclupus erythematosus and immune-related glomerulonephritis and rheumatoidarthritis) and viral infections (such as herpes viruses, pox viruses andadenoviruses), inflammation, graft v. host disease, acute graftrejection, and chronic graft rejection.

In preferred embodiments, polynucleotides, polypeptides, and/orantagonists of the invention are used to inhibit growth, progression,and/or metasis of cancers, in particular those listed above.

Additional diseases or conditions associated with increased cellsurvival that could be treated or detected by polynucleotides orpolypeptides, or agonists or antagonists of the present inventioninclude, but are not limited to, progression, and/or metastases ofmalignancies and related disorders such as leukemia (including acuteleukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia(including myeloblastic, promyelocytic, myelomonocytic, monocytic, anderythroleukemia)) and chronic leukemias (e.g., chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemiavera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease),multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease,and solid tumors including, but not limited to, sarcomas and carcinomassuch as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma,lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma,pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweatgland carcinoma, sebaceous gland carcinoma, papillary carcinoma,papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma,bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile ductcarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor,cervical cancer, testicular tumor, lung carcinoma, small cell lungcarcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma,melanoma, neuroblastoma, and retinoblastoma.

Diseases associated with increased apoptosis that could be treated,prevented, diagnosed, and/or prognesed using polynucleotides orpolypeptides, as well as agonists or antagonists of the presentinvention, include, but are not limited to, AIDS; neurodegenerativedisorders (such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Retinitis pigmentosa, Cerebellar degeneration andbrain tumor or prior associated disease); autoimmune disorders (such as,multiple sclerosis, Sjogren's syndrome, Hashimoto's thyroiditis, biliarycirrhosis, Behcet's disease, Crohn's disease, polymyositis, systemiclupus erythematosus and immune-related glomerulonephritis and rheumatoidarthritis) myelodysplastic syndromes (such as aplastic anemia), graft v.host disease, ischemic injury (such as that caused by myocardialinfarction, stroke and reperfusion injury), liver injury (e.g.,hepatitis related liver injury, ischemia/reperfusion injury, cholestosis(bile duct injury) and liver cancer); toxin-induced liver disease (suchas that caused by alcohol), septic shock, cachexia and anorexia.

Wound Healing and Epithelial Cell Proliferation

In accordance with yet a further aspect of the present invention, thereis provided a process for utilizing polynucleotides or polypeptides, aswell as agonists or antagonists of the present invention, fortherapeutic purposes, for example, to stimulate epithelial cellproliferation and basal keratinocytes for the purpose of wound healing,and to stimulate hair follicle production and healing of dermal wounds.Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, may be clinically useful in stimulating woundhealing including surgical wounds, excisional wounds, deep woundsinvolving damage of the dermis and epidermis, eye tissue wounds, dentaltissue wounds, oral cavity wounds, diabetic ulcers, dermal ulcers,cubitus ulcers, arterial ulcers, venous stasis ulcers, burns resultingfrom heat exposure or chemicals, and other abnormal wound healingconditions such as uremia, malnutrition, vitamin deficiencies andcomplications associated with systemic treatment with steroids,radiation therapy and antineoplastic drugs and antimetabolites.Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could be used to promote dermal reestablishmentsubsequent to dermal loss

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could be used to increase the adherence of skingrafts to a wound bed and to stimulate re-epithelialization from thewound bed. The following are types of grafts that polynucleotides orpolypeptides, agonists or antagonists of the present invention, could beused to increase adherence to a wound bed: autografts, artificial skin,allografts, autodermic graft, autoepdermic grafts, avacular grafts,Blair-Brown grafts, bone graft, brephoplastic grafts, cutis graft,delayed graft, dermic graft, epidermic graft, fascia graft, fullthickness graft, heterologous graft, xenograft, homologous graft,hyperplastic graft, lamellar graft, mesh graft, mucosal graft,Ollier-Thiersch graft, omenpal graft, patch graft, pedicle graft,penetrating graft, split skin graft, thick split graft. Polynucleotidesor polypeptides, as well as agonists or antagonists of the presentinvention, can be used to promote skin strength and to improve theappearance of aged skin.

It is believed that polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, will also produce changes inhepatocyte proliferation, and epithelial cell proliferation in the lung,breast, pancreas, stomach, small intestine, and large intestine.Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could promote proliferation of epithelial cellssuch as sebocytes, hair follicles, hepatocytes, type II pneumocytes,mucin-producing goblet cells, and other epithelial cells and theirprogenitors contained within the skin, lung, liver, and gastrointestinaltract. Polynucleotides or polypeptides, agonists or antagonists of thepresent invention, may promote proliferation of endothelial cells,keratinocytes, and basal keratinocytes.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could also be used to reduce the side effects ofgut toxicity that result from radiation, chemotherapy treatments orviral infections. Polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, may have a cytoprotectiveeffect on the small intestine mucosa. Polynucleotides or polypeptides,as well as agonists or antagonists of the present invention, may alsostimulate healing of mucositis (mouth ulcers) that result fromchemotherapy and viral infections.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could further be used in full regeneration ofskin in full and partial thickness skin defects, including burns, (i.e.,repopulation of hair follicles, sweat glands, and sebaceous glands),treatment of other skin defects such as psoriasis. Polynucleotides orpolypeptides, as well as agonists or antagonists of the presentinvention, could be used to treat epidermolysis bullosa, a defect inadherence of the epidermis to the underlying dermis which results infrequent, open and painful blisters by accelerating reepithelializationof these lesions. Polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, could also be used to treatgastric and doudenal ulcers and help heal by scar formation of themucosal lining and regeneration of glandular mucosa and duodenal mucosallining more rapidly. Inflammatory bowel diseases, such as Crohn'sdisease and ulcerative colitis, are diseases which result in destructionof the mucosal surface of the small or large intestine, respectively.Thus, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used to promote theresurfacing of the mucosal surface to aid more rapid healing and toprevent progression of inflammatory bowel disease. Treatment withpolynucleotides or polypeptides, agonists or antagonists of the presentinvention, is expected to have a significant effect on the production ofmucus throughout the gastrointestinal tract and could be used to protectthe intestinal mucosa from injurious substances that are ingested orfollowing surgery. Polynucleotides or polypeptides, as well as agonistsor antagonists of the present invention, could be used to treat diseasesassociate with the under expression.

Moreover, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used to prevent and healdamage to the lungs due to various pathological states. Polynucleotidesor polypeptides, as well as agonists or antagonists of the presentinvention, which could stimulate proliferation and differentiation andpromote the repair of alveoli and brochiolar epithelium to prevent ortreat acute or chronic lung damage. For example, emphysema, whichresults in the progressive loss of aveoli, and inhalation injuries,i.e., resulting from smoke inhalation and burns, that cause necrosis ofthe bronchiolar epithelium and alveoli could be effectively treatedusing polynucleotides or polypeptides, agonists or antagonists of thepresent invention. Also, polynucleotides or polypeptides, as well asagonists or antagonists of the present invention, could be used tostimulate the proliferation of and differentiation of type IIpneumocytes, which may help treat or prevent disease such as hyalinemembrane diseases, such as infant respiratory distress syndrome andbronchopulmonary displasia, in premature infants.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, could stimulate the proliferation anddifferentiation of hepatocytes and, thus, could be used to alleviate ortreat liver diseases and pathologies such as fulminant liver failurecaused by cirrhosis, liver damage caused by viral hepatitis and toxicsubstances (i.e., acetaminophen, carbon tetraholoride and otherhepatotoxins known in the art).

In addition, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used treat or prevent theonset of diabetes mellitus. In patients with newly diagnosed Types I andII diabetes, where some islet cell function remains, polynucleotides orpolypeptides, as well as agonists or antagonists of the presentinvention, could be used to maintain the islet function so as toalleviate, delay or prevent permanent manifestation of the disease.Also, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, could be used as an auxiliary inislet cell transplantation to improve or promote islet cell function.

Neural Activity and Neurological Diseases

The polynucleotides, polypeptides and agonists or antagonists of theinvention may be used for the diagnosis and/or treatment of diseases,disorders, damage or injury of the brain and/or nervous system. Nervoussystem disorders that can be treated with the compositions of theinvention (e.g., polypeptides, polynucleotides, and/or agonists orantagonists), include, but are not limited to, nervous system injuries,and diseases or disorders which result in either a disconnection ofaxons, a diminution or degeneration of neurons, or demyelination.Nervous system lesions which may be treated in a patient (includinghuman and non-human mammalian patients) according to the methods of theinvention, include but are not limited to, the following lesions ofeither the central (including spinal cord, brain) or peripheral nervoussystems: (1) ischemic lesions, in which a lack of oxygen in a portion ofthe nervous system results in neuronal injury or death, includingcerebral infarction or ischemia, or spinal cord infarction or ischemia;(2) traumatic lesions, including lesions caused by physical injury orassociated with surgery, for example, lesions which sever a portion ofthe nervous system, or compression injuries; (3) malignant lesions, inwhich a portion of the nervous system is destroyed or injured bymalignant tissue which is either a nervous system associated malignancyor a malignancy derived from non-nervous system tissue; (4) infectiouslesions, in which a portion of the nervous system is destroyed orinjured as a result of infection, for example, by an abscess orassociated with infection by human immunodeficiency virus, herpeszoster, or herpes simplex virus or with Lyme disease, tuberculosis, orsyphilis; (5) degenerative lesions, in which a portion of the nervoussystem is destroyed or injured as a result of a degenerative processincluding but not limited to, degeneration associated with Parkinson'sdisease, Alzheimer's disease, Huntington's chorea, or amyotrophiclateral sclerosis (ALS); (6) lesions associated with nutritionaldiseases or disorders, in which a portion of the nervous system isdestroyed or injured by a nutritional disorder or disorder of metabolismincluding, but not limited to, vitamin B12 deficiency, folic aciddeficiency, Wernicke disease, tobacco-alcohol amblyopia,Marchiafava-Bignami disease (primary degeneration of the corpuscallosum), and alcoholic cerebellar degeneration; (7) neurologicallesions associated with systemic diseases including, but not limited to,diabetes (diabetic neuropathy, Bell's palsy), systemic lupuserythematosus, carcinoma, or sarcoidosis; (8) lesions caused by toxicsubstances including alcohol, lead, or particular neurotoxins; and (9)demyelinated lesions in which a portion of the nervous system isdestroyed or injured by a demyelinating disease including, but notlimited to, multiple sclerosis, human immunodeficiency virus-associatedmyelopathy, transverse myelopathy or various etiologies, progressivemultifocal leukoencephalopathy, and central pontine myelinolysis.

In one embodiment, the polypeptides, polynucleotides, or agonists orantagonists of the invention are used to protect neural cells from thedamaging effects of hypoxia. In a further preferred embodiment, thepolypeptides, polynucleotides, or agonists or antagonists of theinvention are used to protect neural cells from the damaging effects ofcerebral hypoxia. According to this embodiment, the compositions of theinvention are used to treat or prevent neural cell injury associatedwith cerebral hypoxia. In one non-exclusive aspect of this embodiment,the polypeptides, polynucleotides, or agonists or antagonists of theinvention, are used to treat or prevent neural cell injury associatedwith cerebral ischemia. In another non-exclusive aspect of thisembodiment, the polypeptides, polynucleotides, or agonists orantagonists of the invention are used to treat or prevent neural cellinjury associated with cerebral infarction.

In another preferred embodiment, the polypeptides, polynucleotides, oragonists or antagonists of the invention are used to treat or preventneural cell injury associated with a stroke. In a specific embodiment,the polypeptides, polynucleotides, or agonists or antagonists of theinvention are used to treat or prevent cerebral neural cell injuryassociated with a stroke.

In another preferred embodiment, the polypeptides, polynucleotides, oragonists or antagonists of the invention are used to treat or preventneural cell injury associated with a heart attack. In a specificembodiment, the polypeptides, polynucleotides, or agonists orantagonists of the invention are used to treat or prevent cerebralneural cell injury associated with a heart attack.

The compositions of the invention which are useful for treating orpreventing a nervous system disorder may be selected by testing forbiological activity in promoting the survival or differentiation ofneurons. For example, and not by way of limitation, compositions of theinvention which elicit any of the following effects may be usefulaccording to the invention: (1) increased survival time of neurons inculture either in the presence or absence of hypoxia or hypoxicconditions; (2) increased sprouting of neurons in culture or in vivo;(3) increased production of a neuron-associated molecule in culture orin vivo, e.g., choline acetyltransferase or acetylcholinesterase withrespect to motor neurons; or (4) decreased symptoms of neurondysfunction in vivo. Such effects may be measured by any method known inthe art. In preferred, non-limiting embodiments, increased survival ofneurons may routinely be measured using a method set forth herein orotherwise known in the art, such as, for example, in Zhang et al., ProcNatl Acad Sci USA 97:3637-42 (2000) or in Arakawa et al., J. Neurosci.,10:3507-15 (1990); increased sprouting of neurons may be detected bymethods known in the art, such as, for example, the methods set forth inPestronk et al., Exp. Neurol., 70:65-82 (1980), or Brown et al., Ann.Rev. Neurosci., 4:17-42 (1981); increased production ofneuron-associated molecules may be measured by bioassay, enzymaticassay, antibody binding, Northern blot assay, etc., using techniquesknown in the art and depending on the molecule to be measured; and motorneuron dysfunction may be measured by assessing the physicalmanifestation of motor neuron disorder, e.g., weakness, motor neuronconduction velocity, or functional disability.

In specific embodiments, motor neuron disorders that may be treatedaccording to the invention include, but are not limited to, disorderssuch as infarction, infection, exposure to toxin, trauma, surgicaldamage, degenerative disease or malignancy that may affect motor neuronsas well as other components of the nervous system, as well as disordersthat selectively affect neurons such as amyotrophic lateral sclerosis,and including, but not limited to, progressive spinal muscular atrophy,progressive bulbar palsy, primary lateral sclerosis, infantile andjuvenile muscular atrophy, progressive bulbar paralysis of childhood(Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, andHereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).

Further, polypeptides or polynucleotides of the invention may play arole in neuronal survival; synapse formation; conductance; neuraldifferentiation, etc. Thus, compositions of the invention (includingpolynucleotides, polypeptides, and agonists or antagonists) may be usedto diagnose and/or treat or prevent diseases or disorders associatedwith these roles, including, but not limited to, learning and/orcognition disorders. The compositions of the invention may also beuseful in the treatment or prevention of neurodegenerative diseasestates and/or behavioural disorders. Such neurodegenerative diseasestates and/or behavioral disorders include, but are not limited to,Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, TouretteSyndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsivedisorder, panic disorder, learning disabilities, ALS, psychoses, autism,and altered behaviors, including disorders in feeding, sleep patterns,balance, and perception. In addition, compositions of the invention mayalso play a role in the treatment, prevention and/or detection ofdevelopmental disorders associated with the developing embryo, orsexually-linked disorders.

Additionally, polypeptides, polynucleotides and/or agonists orantagonists of the invention, may be useful in protecting neural cellsfrom diseases, damage, disorders, or injury, associated withcerebrovascular disorders including, but not limited to, carotid arterydiseases (e.g., carotid artery thrombosis, carotid stenosis, or MoyamoyaDisease), cerebral amyloid angiopathy, cerebral aneurysm, cerebralanoxia, cerebral arteriosclerosis, cerebral arteriovenous malformations,cerebral artery diseases, cerebral embolism and thrombosis (e.g.,carotid artery thrombosis, sinus thrombosis, or Wallenberg's Syndrome),cerebral hemorrhage (e.g., epidural or subdural hematoma, orsubarachnoid hemorrhage), cerebral infarction, cerebral ischemia (e.g.,transient cerebral ischemia, Subclavian Steal Syndrome, orvertebrobasilar insufficiency), vascular dementia (e.g., multi-infarct),leukomalacia, periventricular, and vascular headache (e.g., clusterheadache or migraines).

In accordance with yet a further aspect of the present invention, thereis provided a process for utilizing polynucleotides or polypeptides, aswell as agonists or antagonists of the present invention, fortherapeutic purposes, for example, to stimulate neurological cellproliferation and/or differentiation. Therefore, polynucleotides,polypeptides, agonists and/or antagonists of the invention may be usedto treat and/or detect neurologic diseases. Moreover, polynucleotides orpolypeptides, or agonists or antagonists of the invention, can be usedas a marker or detector of a particular nervous system disease ordisorder.

Examples of neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include brain diseases, such as metabolic braindiseases which includes phenylketonuria such as maternalphenylketonuria, pyruvate carboxylase deficiency, pyruvate dehydrogenasecomplex deficiency, Wernicke's Encephalopathy, brain edema, brainneoplasms such as cerebellar neoplasms which include infratentorialneoplasms, cerebral ventricle neoplasms such as choroid plexusneoplasms, hypothalamic neoplasms, supratentorial neoplasms, canavandisease, cerebellar diseases such as cerebellar ataxia which includespinocerebellar degeneration such as ataxia telangiectasia, cerebellardyssynergia, Friederich's Ataxia, Machado-Joseph Disease,olivopontocerebellar atrophy, cerebellar neoplasms such asinfratentorial neoplasms, diffuse cerebral sclerosis such asencephalitis periaxialis, globoid cell leukodystrophy, metachromaticleukodystrophy and subacute sclerosing panencephalitis.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include cerebrovascular disorders (such as carotidartery diseases which include carotid artery thrombosis, carotidstenosis and Moyamoya Disease), cerebral amyloid angiopathy, cerebralaneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebralarteriovenous malformations, cerebral artery diseases, cerebral embolismand thrombosis such as carotid artery thrombosis, sinus thrombosis andWallenberg's Syndrome, cerebral hemorrhage such as epidural hematoma,subdural hematoma and subarachnoid hemorrhage, cerebral infarction,cerebral ischemia such as transient cerebral ischemia, Subclavian StealSyndrome and vertebrobasilar insufficiency, vascular dementia such asmulti-infarct dementia, periventricular leukomalacia, vascular headachesuch as cluster headache and migraine.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include dementia such as AIDS Dementia Complex,presenile dementia such as Alzheimer's Disease and Creutzfeldt-JakobSyndrome, senile dementia such as Alzheimer's Disease and progressivesupranuclear palsy, vascular dementia such as multi-infarct dementia,encephalitis which include encephalitis periaxialis, viral encephalitissuch as epidemic encephalitis, Japanese Encephalitis, St. LouisEncephalitis, tick-borne encephalitis and West Nile Fever, acutedisseminated encephalomyelitis, meningoencephalitis such asuveomeningoencephalitic syndrome, Postencephalitic Parkinson Disease andsubacute sclerosing panencephalitis, encephalomalacia such asperiventricular leukomalacia, epilepsy such as generalized epilepsywhich includes infantile spasms, absence epilepsy, myoclonic epilepsywhich includes MERRF Syndrome, tonic-clonic epilepsy, partial epilepsysuch as complex partial epilepsy, frontal lobe epilepsy and temporallobe epilepsy, post-traumatic epilepsy, status epilepticus such asEpilepsia Partialis Continua, and Hallervorden-Spatz Syndrome.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include hydrocephalus such as Dandy-Walker Syndromeand normal pressure hydrocephalus, hypothalamic diseases such ashypothalamic neoplasms, cerebral malaria, narcolepsy which includescataplexy, bulbar poliomyelitis, cerebri pseudotumor, Rett Syndrome,Reye's Syndrome, thalamic diseases, cerebral toxoplasmosis, intracranialtuberculoma and Zellweger Syndrome, central nervous system infectionssuch as AIDS Dementia Complex, Brain Abscess, subdural empyema,encephalomyelitis such as Equine Encephalomyelitis, Venezuelan EquineEncephalomyelitis, Necrotizing Hemorrhagic Encephalomyelitis, Visna, andcerebral malaria.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include meningitis such as arachnoiditis, asepticmeningtitis such as viral meningtitis which includes lymphocyticchoriomeningitis, Bacterial meningtitis which includes HaemophilusMeningtitis, Listeria Meningtitis, Meningococcal Meningtitis such asWaterhouse-Friderichsen Syndrome, Pneumococcal Meningtitis and meningealtuberculosis, fungal meningitis such as Cryptococcal Meningtitis,subdural effusion, meningoencephalitis such as uvemeningoencephaliticsyndrome, myelitis such as transverse myelitis, neurosyphilis such astabes dorsalis, poliomyelitis which includes bulbar poliomyelitis andpostpoliomyelitis syndrome, prion diseases (such as Creutzfeldt-JakobSyndrome, Bovine Spongiform Encephalopathy, Gerstmann-StrausslerSyndrome, Kuru, Scrapie), and cerebral toxoplasmosis.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include central nervous system neoplasms such as brainneoplasms that include cerebellar neoplasms such as infratentorialneoplasms, cerebral ventricle neoplasms such as choroid plexusneoplasms, hypothalamic neoplasms and supratentorial neoplasms,meningeal neoplasms, spinal cord neoplasms which include epiduralneoplasms, demyelinating diseases such as Canavan Diseases, diffusecerebral sceloris which includes adrenoleukodystrophy, encephalitisperiaxialis, globoid cell leukodystrophy, diffuse cerebral sclerosissuch as metachromatic leukodystrophy, allergic encephalomyelitis,necrotizing hemorrhagic encephalomyelitis, progressive multifocalleukoencephalopathy, multiple sclerosis, central pontine myelinolysis,transverse myelitis, neuromyelitis optica, Scrapie, Swayback, ChronicFatigue Syndrome, Visna, High Pressure Nervous Syndrome, Meningism,spinal cord diseases such as amyotonia congenita, amyotrophic lateralsclerosis, spinal muscular atrophy such as Werdnig-Hoffmann Disease,spinal cord compression, spinal cord neoplasms such as epiduralneoplasms, syringomyelia, Tabes Dorsalis, Stiff-Man Syndrome, mentalretardation such as Angelman Syndrome, Cri-du-Chat Syndrome, De Lange'sSyndrome, Down Syndrome, Gangliosidoses such as gangliosidoses G(M1),Sandhoff Disease, Tay-Sachs Disease, Hartnup Disease, homocystinuria,Laurence-Moon-Biedl Syndrome, Lesch-Nyhan Syndrome, Maple Syrup UrineDisease, mucolipidosis such as fucosidosis, neuronalceroid-lipofuscinosis, oculocerebrorenal syndrome, phenylketonuria suchas maternal phenylketonuria, Prader-Willi Syndrome, Rett Syndrome,Rubinstein-Taybi Syndrome, Tuberous Sclerosis, WAGR Syndrome, nervoussystem abnormalities such as holoprosencephaly, neural tube defects suchas anencephaly which includes hydrangencephaly, Arnold-Chairi Deformity,encephalocele, meningocele, meningomyelocele, spinal dysraphism such asspina bifida cystica and spina bifida occulta.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include hereditary motor and sensory neuropathieswhich include Charcot-Marie Disease, Hereditary optic atrophy, Refsum'sDisease, hereditary spastic paraplegia, Werdnig-Hoffmann Disease,Hereditary Sensory and Autonomic Neuropathies such as CongenitalAnalgesia and Familial Dysautonomia, Neurologic manifestations (such asagnosia that include Gerstmann's Syndrome, Amnesia such as retrogradeamnesia, apraxia, neurogenic bladder, cataplexy, communicative disorderssuch as hearing disorders that includes deafness, partial hearing loss,loudness recruitment and tinnitus, language disorders such as aphasiawhich include agraphia, anomia, broca aphasia, and Wernicke Aphasia,Dyslexia such as Acquired Dyslexia, language development disorders,speech disorders such as aphasia which includes anomia, broca aphasiaand Wemicke Aphasia, articulation disorders, communicative disorderssuch as speech disorders which include dysarthria, echolalia, mutism andstuttering, voice disorders such as aphonia and hoarseness, decerebratestate, delirium, fasciculation, hallucinations, meningism, movementdisorders such as angelman syndrome, ataxia, athetosis, chorea,dystonia, hypokinesia, muscle hypotonia, myoclonus, tic, torticollis andtremor, muscle hypertonia such as muscle rigidity such as stiff-mansyndrome, muscle spasticity, paralysis such as facial paralysis whichincludes Herpes Zoster Oticus, Gastroparesis, Hemiplegia,ophthalmoplegia such as diplopia, Duane's Syndrome, Horner's Syndrome,Chronic progressive external ophthalmoplegia such as Kearns Syndrome,Bulbar Paralysis, Tropical Spastic Paraparesis, Paraplegia such asBrown-Sequard Syndrome, quadriplegia, respiratory paralysis and vocalcord paralysis, paresis, phantom limb, taste disorders such as ageusiaand dysgeusia, vision disorders such as amblyopia, blindness, colorvision defects, diplopia, hemianopsia, scotoma and subnormal vision,sleep disorders such as hypersomnia which includes Kleine-LevinSyndrome, insomnia, and somnambulism, spasm such as trismus,unconsciousness such as coma, persistent vegetative state and syncopeand vertigo, neuromuscular diseases such as amyotonia congenita,amyotrophic lateral sclerosis, Lambert-Eaton Myasthenic Syndrome, motorneuron disease, muscular atrophy such as spinal muscular atrophy,Charcot-Marie Disease and Werdnig-Hoffmann Disease, PostpoliomyelitisSyndrome, Muscular Dystrophy, Myasthenia Gravis, Myotonia Atrophica,Myotonia Confenita, Nemaline Myopathy, Familial Periodic Paralysis,Multiplex Paramyloclonus, Tropical Spastic Paraparesis and Stiff-ManSyndrome, peripheral nervous system diseases such as acrodynia, amyloidneuropathies, autonomic nervous system diseases such as Adie's Syndrome,Barre-Lieou Syndrome, Familial Dysautonomia, Horner's Syndrome, ReflexSympathetic Dystrophy and Shy-Drager Syndrome, Cranial Nerve Diseasessuch as Acoustic Nerve Diseases such as Acoustic Neuroma which includesNeurofibromatosis 2, Facial Nerve Diseases such as Facial Neuralgia,Melkersson-Rosenthal Syndrome, ocular motility disorders which includesamblyopia, nystagmus, oculomotor nerve paralysis, ophthalmoplegia suchas Duane's Syndrome, Horner's Syndrome, Chronic Progressive ExternalOphthalmoplegia which includes Kearns Syndrome, Strabismus such asEsotropia and Exotropia, Oculomotor Nerve Paralysis, Optic NerveDiseases such as Optic Atrophy which includes Hereditary Optic Atrophy,Optic Disk Drusen, Optic Neuritis such as Neuromyelitis Optica,Papilledema, Trigeminal Neuralgia, Vocal Cord Paralysis, DemyelinatingDiseases such as Neuromyelitis Optica and Swayback, and Diabeticneuropathies such as diabetic foot.

Additional neurologic diseases which can be treated or detected withpolynucleotides, polypeptides, agonists, and/or antagonists of thepresent invention include nerve compression syndromes such as carpaltunnel syndrome, tarsal tunnel syndrome, thoracic outlet syndrome suchas cervical rib syndrome, ulnar nerve compression syndrome, neuralgiasuch as causalgia, cervico-brachial neuralgia, facial neuralgia andtrigeminal neuralgia, neuritis such as experimental allergic neuritis,optic neuritis, polyneuritis, polyradiculoneuritis and radiculities suchas polyradiculitis, hereditary motor and sensory neuropathies such asCharcot-Marie Disease, Hereditary Optic Atrophy, Refsum's Disease,Hereditary Spastic Paraplegia and Werdnig-Hoffmann Disease, HereditarySensory and Autonomic Neuropathies which include Congenital Analgesiaand Familial Dysautonomia, POEMS Syndrome, Sciatica, Gustatory Sweatingand Tetany).

Endocrine Disorders

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention, may be used to treat, prevent, diagnose, and/orprognose disorders and/or diseases related to hormone imbalance, and/ordisorders or diseases of the endocrine system.

Hormones secreted by the glands of the endocrine system control physicalgrowth, sexual function, metabolism, and other functions. Disorders maybe classified in two ways: disturbances in the production of hormones,and the inability of tissues to respond to hormones. The etiology ofthese hormone imbalance or endocrine system diseases, disorders orconditions may be genetic, somatic, such as cancer and some autoimmunediseases, acquired (e.g., by chemotherapy, injury or toxins), orinfectious. Moreover, polynucleotides, polypeptides, antibodies, and/oragonists or antagonists of the present invention can be used as a markeror detector of a particular disease or disorder related to the endocrinesystem and/or hormone imbalance.

Endocrine system and/or hormone imbalance and/or diseases encompassdisorders of uterine motility including, but not limited to:complications with pregnancy and labor (e.g., pre-term labor, post-termpregnancy, spontaneous abortion, and slow or stopped labor); anddisorders and/or diseases of the menstrual cycle (e.g., dysmenorrhea andendometriosis).

Endocrine system and/or hormone imbalance disorders and/or diseasesinclude disorders and/or diseases of the pancreas, such as, for example,diabetes mellitus, diabetes insipidus, congenital pancreatic agenesis,pheochromocytoma—islet cell tumor syndrome; disorders and/or diseases ofthe adrenal glands such as, for example, Addison's Disease,corticosteroid deficiency, virilizing disease, hirsutism, Cushing'sSyndrome, hyperaldosteronism, pheochromocytoma; disorders and/ordiseases of the pituitary gland, such as, for example, hyperpituitarism,hypopituitarism, pituitary dwarfism, pituitary adenoma,panhypopituitarism, acromegaly, gigantism; disorders and/or diseases ofthe thyroid, including but not limited to, hyperthyroidism,hypothyroidism, Plummer's disease, Graves' disease (toxic diffusegoiter), toxic nodular goiter, thyroiditis (Hashimoto's thyroiditis,subacute granulomatous thyroiditis, and silent lymphocytic thyroiditis),Pendred's syndrome, myxedema, cretinism, thyrotoxicosis, thyroid hormonecoupling defect, thymic aplasia, Hurthle cell tumours of the thyroid,thyroid cancer, thyroid carcinoma, Medullary thyroid carcinoma;disorders and/or diseases of the parathyroid, such as, for example,hyperparathyroidism, hypoparathyroidism; disorders and/or diseases ofthe hypothalamus.

In addition, endocrine system and/or hormone imbalance disorders and/ordiseases may also include disorders and/or diseases of the testes orovaries, including cancer. Other disorders and/or diseases of the testesor ovaries further include, for example, ovarian cancer, polycysticovary syndrome, Klinefelter's syndrome, vanishing testes syndrome(bilateral anorchia), congenital absence of Leydig's cells,cryptorchidism, Noonan's syndrome, myotonic dystrophy, capillaryhaemangioma of the testis (benign), neoplasias of the testis andneo-testis.

Moreover, endocrine system and/or hormone imbalance disorders and/ordiseases may also include disorders and/or diseases such as, forexample, polyglandular deficiency syndromes, pheochromocytoma,neuroblastoma, multiple Endocrine neoplasia, and disorders and/orcancers of endocrine tissues.

In another embodiment, a polypeptide of the invention, orpolynucleotides, antibodies, agonists, or antagonists corresponding tothat polypeptide, may be used to diagnose, prognose, prevent, and/ortreat endocrine diseases and/or disorders associated with the tissue(s)in which the polypeptide of the invention is expressed, including one,two, three, four, five, or more tissues disclosed in Table 1B.2, column5 (Tissue Distribution Library Code).

Reproductive System Disorders

The polynucleotides or polypeptides, or agonists or antagonists of theinvention may be used for the diagnosis, treatment, or prevention ofdiseases and/or disorders of the reproductive system. Reproductivesystem disorders that can be treated by the compositions of theinvention, include, but are not limited to, reproductive systeminjuries, infections, neoplastic disorders, congenital defects, anddiseases or disorders which result in infertility, complications withpregnancy, labor, or parturition, and postpartum difficulties.

Reproductive system disorders and/or diseases include diseases and/ordisorders of the testes, including testicular atrophy, testicularfeminization, cryptorchism (unilateral and bilateral), anorchia, ectopictestis, epididymitis and orchitis (typically resulting from infectionssuch as, for example, gonorrhea, mumps, tuberculosis, and syphilis),testicular torsion, vasitis nodosa, germ cell tumors (e.g., seminomas,embryonal cell carcinomas, teratocarcinomas, choriocarcinomas, yolk sactumors, and teratomas), stromal tumors (e.g., Leydig cell tumors),hydrocele, hematocele, varicocele, spermatocele, inguinal hernia, anddisorders of sperm production (e.g., immotile cilia syndrome, aspermia,asthenozoospermia, azoospermia, oligospermia, and teratozoospermia).

Reproductive system disorders also include disorders of the prostategland, such as acute non-bacterial prostatitis, chronic non-bacterialprostatitis, acute bacterial prostatitis, chronic bacterial prostatitis,prostatodystonia, prostatosis, granulomatous prostatitis, malacoplakia,benign prostatic hypertrophy or hyperplasia, and prostate neoplasticdisorders, including adenocarcinomas, transitional cell carcinomas,ductal carcinomas, and squamous cell carcinomas.

Additionally, the compositions of the invention may be useful in thediagnosis, treatment, and/or prevention of disorders or diseases of thepenis and urethra, including inflammatory disorders, such asbalanoposthitis, balanitis xerotica obliterans, phimosis, paraphimosis,syphilis, herpes simplex virus, gonorrhea, non-gonococcal urethritis,chlamydia, mycoplasma, trichomonas, HIV, AIDS, Reiter's syndrome,condyloma acuminatum, condyloma latum, and pearly penile papules;urethral abnormalities, such as hypospadias, epispadias, and phimosis;premalignant lesions, including Erythroplasia of Queyrat, Bowen'sdisease, Bowenoid paplosis, giant condyloma of Buscke-Lowenstein, andvarrucous carcinoma; penile cancers, including squamous cell carcinomas,carcinoma in situ, verrucous carcinoma, and disseminated penilecarcinoma; urethral neoplastic disorders, including penile urethralcarcinoma, bulbomembranous urethral carcinoma, and prostatic urethralcarcinoma; and erectile disorders, such as priapism, Peyronie's disease,erectile dysfunction, and impotence.

Moreover, diseases and/or disorders of the vas deferens includevasculititis and CBAVD (congenital bilateral absence of the vasdeferens); additionally, the polynucleotides, polypeptides, and agonistsor antagonists of the present invention may be used in the diagnosis,treatment, and/or prevention of diseases and/or disorders of the seminalvesicles, including hydatid disease, congenital chloride diarrhea, andpolycystic kidney disease.

Other disorders and/or diseases of the male reproductive system include,for example, Klinefelter's syndrome, Young's syndrome, prematureejaculation, diabetes mellitus, cystic fibrosis, Kartagener's syndrome,high fever, multiple sclerosis, and gynecomastia.

Further, the polynucleotides, polypeptides, and agonists or antagonistsof the present invention may be used in the diagnosis, treatment, and/orprevention of diseases and/or disorders of the vagina and vulva,including bacterial vaginosis, candida vaginitis, herpes simplex virus,chancroid, granuloma inguinale, lymphogranuloma venereum, scabies, humanpapillomavirus, vaginal trauma, vulvar trauma, adenosis, chlamydiavaginitis, gonorrhea, trichomonas vaginitis, condyloma acuminatum,syphilis, molluscum contagiosum, atrophic vaginitis, Paget's disease,lichen sclerosus, lichen planus, vulvodynia, toxic shock syndrome,vaginismus, vulvovaginitis, vulvar vestibulitis, and neoplasticdisorders, such as squamous cell hyperplasia, clear cell carcinoma,basal cell carcinoma, melanomas, cancer of Bartholin's gland, and vulvarintraepithelial neoplasia.

Disorders and/or diseases of the uterus include dysmenorrhea,retroverted uterus, endometriosis, fibroids, adenomyosis, anovulatorybleeding, amenorrhea, Cushing's syndrome, hydatidiform moles, Asherman'ssyndrome, premature menopause, precocious puberty, uterine polyps,dysfunctional uterine bleeding (e.g., due to aberrant hormonal signals),and neoplastic disorders, such as adenocarcinomas, keiomyosarcomas, andsarcomas. Additionally, the polypeptides, polynucleotides, or agonistsor antagonists of the invention may be useful as a marker or detectorof, as well as in the diagnosis, treatment, and/or prevention ofcongenital uterine abnormalities, such as bicornuate uterus, septateuterus, simple unicornuate uterus, unicornuate uterus with a noncavitaryrudimentary horn, unicornuate uterus with a non-communicating cavitaryrudimentary horn, unicornuate uterus with a communicating cavitary horn,arcuate uterus, uterine didelfus, and T-shaped uterus.

Ovarian diseases and/or disorders include anovulation, polycystic ovarysyndrome (Stein-Leventhal syndrome), ovarian cysts, ovarianhypofunction, ovarian insensitivity to gonadotropins, ovarianoverproduction of androgens, right ovarian vein syndrome, amenorrhea,hirutism, and ovarian cancer (including, but not limited to, primary andsecondary cancerous growth, Sertoli-Leydig tumors, endometriod carcinomaof the ovary, ovarian papillary serous adenocarcinoma, ovarian mucinousadenocarcinoma, and Ovarian Krukenberg tumors).

Cervical diseases and/or disorders include cervicitis, chroniccervicitis, mucopurulent cervicitis, cervical dysplasia, cervicalpolyps, Nabothian cysts, cervical erosion, cervical incompetence, andcervical neoplasms (including, for example, cervical carcinoma, squamousmetaplasia, squamous cell carcinoma, adenosquamous cell neoplasia, andcolumnar cell neoplasia).

Additionally, diseases and/or disorders of the reproductive systeminclude disorders and/or diseases of pregnancy, including miscarriageand stillbirth, such as early abortion, late abortion, spontaneousabortion, induced abortion, therapeutic abortion, threatened abortion,missed abortion, incomplete abortion, complete abortion, habitualabortion, missed abortion, and septic abortion; ectopic pregnancy,anemia, Rh incompatibility, vaginal bleeding during pregnancy,gestational diabetes, intrauterine growth retardation, polyhydramnios,HELLP syndrome, abruptio placentae, placenta previa, hyperemesis,preeclampsia, eclampsia, herpes gestationis, and urticaria of pregnancy.Additionally, the polynucleotides, polypeptides, and agonists orantagonists of the present invention may be used in the diagnosis,treatment, and/or prevention of diseases that can complicate pregnancy,including heart disease, heart failure, rheumatic heart disease,congenital heart disease, mitral valve prolapse, high blood pressure,anemia, kidney disease, infectious disease (e.g., rubella,cytomegalovirus, toxoplasmosis, infectious hepatitis, chlamydia, HIV,AIDS, and genital herpes), diabetes mellitus, Graves' disease,thyroiditis, hypothyroidism, Hashimoto's thyroiditis, chronic activehepatitis, cirrhosis of the liver, primary biliary cirrhosis, asthma,systemic lupus eryematosis, rheumatoid arthritis, myasthenia gravis,idiopathic thrombocytopenic purpura, appendicitis, ovarian cysts,gallbladder disorders, and obstruction of the intestine.

Complications associated with labor and parturition include prematurerupture of the membranes, pre-term labor, post-term pregnancy,postmaturity, labor that progresses too slowly, fetal distress (e.g.,abnormal heart rate (fetal or maternal), breathing problems, andabnormal fetal position), shoulder dystocia, prolapsed umbilical cord,amniotic fluid embolism, and aberrant uterine bleeding.

Further, diseases and/or disorders of the postdelivery period, includingendometritis, myometritis, parametritis, peritonitis, pelvicthrombophlebitis, pulmonary embolism, endotoxemia, pyelonephritis,saphenous thrombophlebitis, mastitis, cystitis, postpartum hemorrhage,and inverted uterus.

Other disorders and/or diseases of the female reproductive system thatmay be diagnosed, treated, and/or prevented by the polynucleotides,polypeptides, and agonists or antagonists of the present inventioninclude, for example, Turner's syndrome, pseudohermaphroditism,premenstrual syndrome, pelvic inflammatory disease, pelvic congestion(vascular engorgement), frigidity, anorgasmia, dyspareunia, rupturedfallopian tube, and Mittelschmerz.

Infectious Disease

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention can be used to treat or detect infectious agents.For example, by increasing the immune response, particularly increasingthe proliferation and differentiation of B and/or T cells, infectiousdiseases may be treated. The immune response may be increased by eitherenhancing an existing immune response, or by initiating a new immuneresponse. Alternatively, polynucleotides or polypeptides, as well asagonists or antagonists of the present invention may also directlyinhibit the infectious agent, without necessarily eliciting an immuneresponse.

Viruses are one example of an infectious agent that can cause disease orsymptoms that can be treated or detected by a polynucleotide orpolypeptide and/or agonist or antagonist of the present invention.Examples of viruses, include, but are not limited to Examples ofviruses, include, but are not limited to the following DNA and RNAviruses and viral families: Arbovirus, Adenoviridae, Arenaviridae,Arterivirus, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae,Coronaviridae, Dengue, EBV, HIV, Flaviviridae, Hepadnaviridae(Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex,Herpes Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus,Rhabdoviridae), Orthomyxoviridae (e.g., Influenza A, Influenza B, andparainfluenza), Papiloma virus, Papovaviridae, Parvoviridae,Picornaviridae, Poxyiridae (such as Smallpox or Vaccinia), Reoviridae(e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), andTogaviridae (e.g., Rubivirus). Viruses falling within these families cancause a variety of diseases or symptoms, including, but not limited to:arthritis, bronchiollitis, respiratory syncytial virus, encephalitis,eye infections (e.g., conjunctivitis, keratitis), chronic fatiguesyndrome, hepatitis (A, B, C, E, Chronic Active, Delta), Japanese Bencephalitis, Junin, Chikungunya, Rift Valley fever, yellow fever,meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt'sLymphoma, chickenpox, hemorrhagic fever, Measles, Mumps, Parainfluenza,Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitteddiseases, skin diseases (e.g., Kaposi's, warts), and viremia.polynucleotides or polypeptides, or agonists or antagonists of theinvention, can be used to treat or detect any of these symptoms ordiseases. In specific embodiments, polynucleotides, polypeptides, oragonists or antagonists of the invention are used to treat: meningitis,Dengue, EBV, and/or hepatitis (e.g., hepatitis B). In an additionalspecific embodiment polynucleotides, polypeptides, or agonists orantagonists of the invention are used to treat patients nonresponsive toone or more other commercially available hepatitis vaccines. In afurther specific embodiment polynucleotides, polypeptides, or agonistsor antagonists of the invention are used to treat AIDS.

Similarly, bacterial and fungal agents that can cause disease orsymptoms and that can be treated or detected by a polynucleotide orpolypeptide and/or agonist or antagonist of the present inventioninclude, but not limited to, the following Gram-Negative andGram-positive bacteria, bacterial families, and fungi: Actinomyces(e.g., Norcardia), Acinetobacter, Cryptococcus neoformans, Aspergillus,Bacillaceae (e.g., Bacillus anthrasis), Bacteroides (e.g., Bacteroidesfragilis), Blastomycosis, Bordetella, Borrelia (e.g., Borreliaburgdorferi), Brucella, Candidia, Campylobacter, Chlamydia, Clostridium(e.g., Clostridium botulinum, Clostridium dificile, Clostridiumperfringens, Clostridium tetani), Coccidioides, Corynebacterium (e.g.,Corynebacterium diptheriae), Cryptococcus, Dermatocycoses, E. coli(e.g., Enterotoxigenic E. coli and Enterohemorrhagic E. coli),Enterobacter (e.g. Enterobacter aerogenes), Enterobacteriaceae(Klebsiella, Salmonella (e.g., Salmonella typhi, Salmonella enteritidis,Salmonella typhi), Serratia, Yersinia, Shigella), Erysipelothrix,Haemophilus (e.g., Haemophilus influenza type B), Helicobacter,Legionella (e.g., Legionella pneumophila), Leptospira, Listeria (e.g.,Listeria monocytogenes), Mycoplasma, Mycobacterium (e.g., Mycobacteriumleprae and Mycobacterium tuberculosis), Vibrio (e.g., Vibrio cholerae),Neisseriaceae (e.g., Neisseria gonorrhea, Neisseria meningitidis),Pasteurellacea, Proteus, Pseudomonas (e.g., Pseudomonas aeruginosa),Rickettsiaceae, Spirochetes (e.g., Treponema spp., Leptospira spp.,Borrelia spp.), Shigella spp., Staphylococcus (e.g., Staphylococcusaureus), Meningiococcus, Pneumococcus and Streptococcus (e.g.,Streptococcus pneumoniae and Groups A, B, and C Streptococci), andUreaplasmas. These bacterial, parasitic, and fungal families can causediseases or symptoms, including, but not limited to:antibiotic-resistant infections, bacteremia, endocarditis, septicemia,eye infections (e.g., conjunctivitis), uveitis, tuberculosis,gingivitis, bacterial diarrhea, opportunistic infections (e.g., AIDSrelated infections), paronychia, prosthesis-related infections, dentalcaries, Reiter's Disease, respiratory tract infections, such as WhoopingCough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, dysentery,paratyphoid fever, food poisoning, Legionella disease, chronic and acuteinflammation, erythema, yeast infections, typhoid, pneumonia, gonorrhea,meningitis (e.g., mengitis types A and B), chlamydia, syphillis,diphtheria, leprosy, brucellosis, peptic ulcers, anthrax, spontaneousabortions, birth defects, pneumonia, lung infections, ear infections,deafness, blindness, lethargy, malaise, vomiting, chronic diarrhea,Crohn's disease, colitis, vaginosis, sterility, pelvic inflammatorydiseases, candidiasis, paratuberculosis, tuberculosis, lupus, botulism,gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexuallytransmitted diseases, skin diseases (e.g., cellulitis, dermatocycoses),toxemia, urinary tract infections, wound infections, noscomialinfections. Polynucleotides or polypeptides, agonists or antagonists ofthe invention, can be used to treat or detect any of these symptoms ordiseases. In specific embodiments, polynucleotides, polypeptides,agonists or antagonists of the invention are used to treat: tetanus,diptheria, botulism, and/or meningitis type B.

Moreover, parasitic agents causing disease or symptoms that can betreated, prevented, and/or diagnosed by a polynucleotide or polypeptideand/or agonist or antagonist of the present invention include, but notlimited to, the following families or class: Amebiasis, Babesiosis,Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic,Giardias, Helminthiasis, Leishmaniasis, Schistisoma, Theileriasis,Toxoplasmosis, Trypanosomiasis, and Trichomonas and Sporozoans (e.g.,Plasmodium virax, Plasmodium falciparium, Plasmodium malariae andPlasmodium ovale). These parasites can cause a variety of diseases orsymptoms, including, but not limited to: Scabies, Trombiculiasis, eyeinfections, intestinal disease (e.g., dysentery, giardiasis), liverdisease, lung disease, opportunistic infections (e.g., AIDS related),malaria, pregnancy complications, and toxoplasmosis. polynucleotides orpolypeptides, or agonists or antagonists of the invention, can be usedto treat, prevent, and/or diagnose any of these symptoms or diseases. Inspecific embodiments, polynucleotides, polypeptides, or agonists orantagonists of the invention are used to treat, prevent, and/or diagnosemalaria.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention of the present invention could either be byadministering an effective amount of a polypeptide to the patient, or byremoving cells from the patient, supplying the cells with apolynucleotide of the present invention, and returning the engineeredcells to the patient (ex vivo therapy). Moreover, the polypeptide orpolynucleotide of the present invention can be used as an antigen in avaccine to raise an immune response against infectious disease.

Regeneration

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention can be used to differentiate, proliferate, andattract cells, leading to the regeneration of tissues. (See, Science276:59-87 (1997)). The regeneration of tissues could be used to repair,replace, or protect tissue damaged by congenital defects, trauma(wounds, burns, incisions, or ulcers), age, disease (e.g. osteoporosis,osteocarthritis, periodontal disease, liver failure), surgery, includingcosmetic plastic surgery, fibrosis, reperfusion injury, or systemiccytokine damage.

Tissues that could be regenerated using the present invention includeorgans (e.g., pancreas, liver, intestine, kidney, skin, endothelium),muscle (smooth, skeletal or cardiac), vasculature (including vascularand lymphatics), nervous, hematopoietic, and skeletal (bone, cartilage,tendon, and ligament) tissue. Preferably, regeneration occurs without ordecreased scarring. Regeneration also may include angiogenesis.

Moreover, polynucleotides or polypeptides, as well as agonists orantagonists of the present invention, may increase regeneration oftissues difficult to heal. For example, increased tendon/ligamentregeneration would quicken recovery time after damage. Polynucleotidesor polypeptides, as well as agonists or antagonists of the presentinvention could also be used prophylactically in an effort to avoiddamage. Specific diseases that could be treated include of tendinitis,carpal tunnel syndrome, and other tendon or ligament defects. A furtherexample of tissue regeneration of non-healing wounds includes pressureulcers, ulcers associated with vascular insufficiency, surgical, andtraumatic wounds.

Similarly, nerve and brain tissue could also be regenerated by usingpolynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention, to proliferate and differentiate nerve cells.Diseases that could be treated using this method include central andperipheral nervous system diseases, neuropathies, or mechanical andtraumatic disorders (e.g., spinal cord disorders, head trauma,cerebrovascular disease, and stoke). Specifically, diseases associatedwith peripheral nerve injuries, peripheral neuropathy (e.g., resultingfrom chemotherapy or other medical therapies), localized neuropathies,and central nervous system diseases (e.g., Alzheimer's disease,Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, and Shy-Drager syndrome), could all be treated using thepolynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention.

Gastrointestinal Disorders

Polynucleotides or polypeptides, or agonists or antagonists of thepresent invention, may be used to treat, prevent, diagnose, and/orprognose gastrointestinal disorders, including inflammatory diseasesand/or conditions, infections, cancers (e.g., intestinal neoplasms(carcinoid tumor of the small intestine, non-Hodgkin's lymphoma of thesmall intestine, small bowl lymphoma)), and ulcers, such as pepticulcers.

Gastrointestinal disorders include dysphagia, odynophagia, inflammationof the esophagus, peptic esophagitis, gastric reflux, submucosalfibrosis and stricturing, Mallory-Weiss lesions, leiomyomas, lipomas,epidermal cancers, adeoncarcinomas, gastric retention disorders,gastroenteritis, gastric atrophy, gastric/stomach cancers, polyps of thestomach, autoimmune disorders such as pernicious anemia, pyloricstenosis, gastritis (bacterial, viral, eosinophilic, stress-induced,chronic erosive, atrophic, plasma cell, and Ménétrier's), and peritonealdiseases (e.g., chyloperioneum, hemoperitoneum, mesenteric cyst,mesenteric lymphadenitis, mesenteric vascular occlusion, panniculitis,neoplasms, peritonitis, pneumoperitoneum, bubphrenic abscess,).

Gastrointestinal disorders also include disorders associated with thesmall intestine, such as malabsorption syndromes, distension, irritablebowel syndrome, sugar intolerance, celiac disease, duodenal ulcers,duodenitis, tropical sprue, Whipple's disease, intestinallymphangiectasia, Crohn's disease, appendicitis, obstructions of theileum, Meckel's diverticulum, multiple diverticula, failure of completerotation of the small and large intestine, lymphoma, and bacterial andparasitic diseases (such as Traveler's diarrhea, typhoid andparatyphoid, cholera, infection by Roundworms (Ascariasis lumbricoides),Hookworms (Ancylostoma duodenale), Threadworms (Enterobiusvermicularis), Tapeworms (Taenia saginata, Echinococcus granulosus,Diphyllobothrium spp., and T. solium).

Liver diseases and/or disorders include intrahepatic cholestasis(alagille syndrome, biliary liver cirrhosis), fatty liver (alcoholicfatty liver, reye syndrome), hepatic vein thrombosis, hepatolentriculardegeneration, hepatomegaly, hepatopulmonary syndrome, hepatorenalsyndrome, portal hypertension (esophageal and gastric varices), liverabscess (amebic liver abscess), liver cirrhosis (alcoholic, biliary andexperimental), alcoholic liver diseases (fatty liver, hepatitis,cirrhosis), parasitic (hepatic echinococcosis, fascioliasis, amebicliver abscess), jaundice (hemolytic, hepatocellular, and cholestatic),cholestasis, portal hypertension, liver enlargement, ascites, hepatitis(alcoholic hepatitis, animal hepatitis, chronic hepatitis (autoimmune,hepatitis B, hepatitis C, hepatitis D, drug induced), toxic hepatitis,viral human hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitisD, hepatitis E), Wilson's disease, granulomatous hepatitis, secondarybiliary cirrhosis, hepatic encephalopathy, portal hypertension, varices,hepatic encephalopathy, primary biliary cirrhosis, primary sclerosingcholangitis, hepatocellular adenoma, hemangiomas, bile stones, liverfailure (hepatic encephalopathy, acute liver failure), and liverneoplasms (angiomyolipoma, calcified liver metastases, cystic livermetastases, epithelial tumors, fibrolamellar hepatocarcinoma, focalnodular hyperplasia, hepatic adenoma, hepatobiliary cystadenoma,hepatoblastoma, hepatocellular carcinoma, hepatoma, liver cancer, liverhemangioendothelioma, mesenchymal hamartoma, mesenchymal tumors ofliver, nodular regenerative hyperplasia, benign liver tumors (Hepaticcysts [Simple cysts, Polycystic liver disease, Hepatobiliarycystadenoma, Choledochal cyst], Mesenchymal tumors [Mesenchymalhamartoma, Infantile hemangioendothelioma, Hemangioma, Peliosis hepatis,Lipomas, Inflammatory pseudotumor, Miscellaneous], Epithelial tumors[Bile duct epithelium (Bile duct hamartoma, Bile duct adenoma),Hepatocyte (Adenoma, Focal nodular hyperplasia, Nodular regenerativehyperplasia)], malignant liver tumors [hepatocellular, hepatoblastoma,hepatocellular carcinoma, cholangiocellular, cholangiocarcinoma,cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi'ssarcoma, hemangioendothelioma, other tumors, embryonal sarcoma,fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma,teratoma, carcinoid, squamous carcinoma, primary lymphoma]), peliosishepatis, erythrohepatic porphyria, hepatic porphyria (acute intermittentporphyria, porphyria cutanea tarda), Zellweger syndrome).

Pancreatic diseases and/or disorders include acute pancreatitis, chronicpancreatitis (acute necrotizing pancreatitis, alcoholic pancreatitis),neoplasms (adenocarcinoma of the pancreas, cystadenocarcinoma,insulinoma, gastrinoma, and glucagonoma, cystic neoplasms, islet-celltumors, pancreoblastoma), and other pancreatic diseases (e.g., cysticfibrosis, cyst (pancreatic pseudocyst, pancreatic fistula,insufficiency)).

Gallbladder diseases include gallstones (cholelithiasis andcholedocholithiasis), postcholecystectomy syndrome, diverticulosis ofthe gallbladder, acute cholecystitis, chronic cholecystitis, bile ducttumors, and mucocele.

Diseases and/or disorders of the large intestine includeantibiotic-associated colitis, diverticulitis, ulcerative colitis,acquired megacolon, abscesses, fungal and bacterial infections,anorectal disorders (e.g., fissures, hemorrhoids), colonic diseases(colitis, colonic neoplasms [colon cancer, adenomatous colon polyps(e.g., villous adenoma), colon carcinoma, colorectal cancer], colonicdiverticulitis, colonic diverticulosis, megacolon [Hirschsprung disease,toxic megacolon]; sigmoid diseases [proctocolitis, sigmoin neoplasms]),constipation, Crohn's disease, diarrhea (infantile diarrhea, dysentery),duodenal diseases (duodenal neoplasms, duodenal obstruction, duodenalulcer, duodenitis), enteritis (enterocolitis), HIV enteropathy, ilealdiseases (ileal neoplasms, ileitis), immunoproliferative smallintestinal disease, inflammatory bowel disease (ulcerative colitis,Crohn's disease), intestinal atresia, parasitic diseases (anisakiasis,balantidiasis, blastocystis infections, cryptosporidiosis,dientamoebiasis, amebic dysentery, giardiasis), intestinal fistula(rectal fistula), intestinal neoplasms (cecal neoplasms, colonicneoplasms, duodenal neoplasms, ileal neoplasms, intestinal polyps,jejunal neoplasms, rectal neoplasms), intestinal obstruction (afferentloop syndrome, duodenal obstruction, impacted feces, intestinalpseudo-obstruction [cecal volvulus], intussusception), intestinalperforation, intestinal polyps (colonic polyps, gardner syndrome,peutz-jeghers syndrome), jejunal diseases (jejunal neoplasms),malabsorption syndromes (blind loop syndrome, celiac disease, lactoseintolerance, short bowl syndrome, tropical sprue, whipple's disease),mesenteric vascular occlusion, pneumatosis cystoides intestinalis,protein-losing enteropathies (intestinal lymphagiectasis), rectaldiseases (anus diseases, fecal incontinence, hemorrhoids, proctitis,rectal fistula, rectal prolapse, rectocele), peptic ulcer (duodenalulcer, peptic esophagitis, hemorrhage, perforation, stomach ulcer,Zollinger-Ellison syndrome), postgastrectomy syndromes (dumpingsyndrome), stomach diseases (e.g., achlorhydria, duodenogastric reflux(bile reflux), gastric antral vascular ectasia, gastric fistula, gastricoutlet obstruction, gastritis (atrophic or hypertrophic), gastroparesis,stomach dilatation, stomach diverticulum, stomach neoplasms (gastriccancer, gastric polyps, gastric adenocarcinoma, hyperplastic gastricpolyp), stomach rupture, stomach ulcer, stomach volvulus), tuberculosis,visceroptosis, vomiting (e.g., hematemesis, hyperemesis gravidarum,postoperative nausea and vomiting) and hemorrhagic colitis.

Further diseases and/or disorders of the gastrointestinal system includebiliary tract diseases, such as, gastroschisis, fistula (e.g., biliaryfistula, esophageal fistula, gastric fistula, intestinal fistula,pancreatic fistula), neoplasms (e.g., biliary tract neoplasms,esophageal neoplasms, such as adenocarcinoma of the esophagus,esophageal squamous cell carcinoma, gastrointestinal neoplasms,pancreatic neoplasms, such as adenocarcinoma of the pancreas, mucinouscystic neoplasm of the pancreas, pancreatic cystic neoplasms,pancreatoblastoma, and peritoneal neoplasms), esophageal disease (e.g.,bullous diseases, candidiasis, glycogenic acanthosis, ulceration,barrett esophagus varices, atresia, cyst, diverticulum (e.g., Zenker'sdiverticulum), fistula (e.g., tracheoesophageal fistula), motilitydisorders (e.g., CREST syndrome, deglutition disorders, achalasia,spasm, gastroesophageal reflux), neoplasms, perforation (e.g., Boerhaavesyndrome, Mallory-Weiss syndrome), stenosis, esophagitis, diaphragmatichernia (e.g., hiatal hernia); gastrointestinal diseases, such as,gastroenteritis (e.g., cholera morbus, norwalk virus infection),hemorrhage (e.g., hematemesis, melena, peptic ulcer hemorrhage), stomachneoplasms (gastric cancer, gastric polyps, gastric adenocarcinoma,stomach cancer)), hernia (e.g., congenital diaphragmatic hernia, femoralhernia, inguinal hernia, obturator hernia, umbilical hernia, ventralhernia), and intestinal diseases (e.g., cecal diseases (appendicitis,cecal neoplasms)).

Chemotaxis

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention may have chemotaxis activity. A chemotaxicmolecule attracts or mobilizes cells (e.g., monocytes, fibroblasts,neutrophils, T-cells, mast cells, eosinophils, epithelial and/orendothelial cells) to a particular site in the body, such asinflammation, infection, or site of hyperproliferation. The mobilizedcells can then fight off and/or heal the particular trauma orabnormality.

Polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention may increase chemotaxic activity of particularcells. These chemotactic molecules can then be used to treatinflammation, infection, hyperproliferative disorders, or any immunesystem disorder by increasing the number of cells targeted to aparticular location in the body. For example, chemotaxic molecules canbe used to treat wounds and other trauma to tissues by attracting immunecells to the injured location. Chemotactic molecules of the presentinvention can also attract fibroblasts, which can be used to treatwounds.

It is also contemplated that polynucleotides or polypeptides, as well asagonists or antagonists of the present invention may inhibit chemotacticactivity. These molecules could also be used to treat disorders. Thus,polynucleotides or polypeptides, as well as agonists or antagonists ofthe present invention could be used as an inhibitor of chemotaxis.

Binding Activity

A polypeptide of the present invention may be used to screen formolecules that bind to the polypeptide or for molecules to which thepolypeptide binds. The binding of the polypeptide and the molecule mayactivate (agonist), increase, inhibit (antagonist), or decrease activityof the polypeptide or the molecule bound. Examples of such moleculesinclude antibodies, oligonucleotides, proteins (e.g., receptors), orsmall molecules.

Preferably, the molecule is closely related to the natural ligand of thepolypeptide, e.g., a fragment of the ligand, or a natural substrate, aligand, a structural or functional mimetic. (See, Coligan et al.,Current Protocols in Immunology 1(2):Chapter 5 (1991)). Similarly, themolecule can be closely related to the natural receptor to which thepolypeptide binds, or at least, a fragment of the receptor capable ofbeing bound by the polypeptide (e.g., active site). In either case, themolecule can be rationally designed using known techniques.

Preferably, the screening for these molecules involves producingappropriate cells which express the polypeptide. Preferred cells includecells from mammals, yeast, Drosophila, or E. coli. Cells expressing thepolypeptide (or cell membrane containing the expressed polypeptide) arethen preferably contacted with a test compound potentially containingthe molecule to observe binding, stimulation, or inhibition of activityof either the polypeptide or the molecule.

The assay may simply test binding of a candidate compound to thepolypeptide, wherein binding is detected by a label, or in an assayinvolving competition with a labeled competitor. Further, the assay maytest whether the candidate compound results in a signal generated bybinding to the polypeptide.

Alternatively, the assay can be carried out using cell-freepreparations, polypeptide/molecule affixed to a solid support, chemicallibraries, or natural product mixtures. The assay may also simplycomprise the steps of mixing a candidate compound with a solutioncontaining a polypeptide, measuring polypeptide/molecule activity orbinding, and comparing the polypeptide/molecule activity or binding to astandard.

Preferably, an ELISA assay can measure polypeptide level or activity ina sample (e.g., biological sample) using a monoclonal or polyclonalantibody. The antibody can measure polypeptide level or activity byeither binding, directly or indirectly, to the polypeptide or bycompeting with the polypeptide for a substrate.

Additionally, the receptor to which the polypeptide of the presentinvention binds can be identified by numerous methods known to those ofskill in the art, for example, ligand panning and FACS sorting (Coligan,et al., Current Protocols in Immun., 1(2), Chapter 5, (1991)). Forexample, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the polypeptides, for example, NIH3T3cells which are known to contain multiple receptors for the FGF familyproteins, and SC-3 cells, and a cDNA library created from this RNA isdivided into pools and used to transfect COS cells or other cells thatare not responsive to the polypeptides. Transfected cells which aregrown on glass slides are exposed to the polypeptide of the presentinvention, after they have been labeled. The polypeptides can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase.

Following fixation and incubation, the slides are subjected toauto-radiographic analysis. Positive pools are identified and sub-poolsare prepared and re-transfected using an iterative sub-pooling andre-screening process, eventually yielding a single clones that encodesthe putative receptor.

As an alternative approach for receptor identification, the labeledpolypeptides can be photoaffinity linked with cell membrane or extractpreparations that express the receptor molecule. Cross-linked materialis resolved by PAGE analysis and exposed to X-ray film. The labeledcomplex containing the receptors of the polypeptides can be excised,resolved into peptide fragments, and subjected to proteinmicrosequencing. The amino acid sequence obtained from microsequencingwould be used to design a set of degenerate oligonucleotide probes toscreen a cDNA library to identify the genes encoding the putativereceptors.

Moreover, the techniques of gene-shuffling, motif-shuffling,exon-shuffling, and/or codon-shuffling (collectively referred to as “DNAshuffling”) may be employed to modulate the activities of thepolypeptide of the present invention thereby effectively generatingagonists and antagonists of the polypeptide of the present invention.See generally, U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721,5,834,252, and 5,837,458, and Patten, P. A., et al., Curr. OpinionBiotechnol. 8:724-33 (1997); Harayama, S. Trends Biotechnol. 16(2):76-82(1998); Hansson, L. O., et al., J. Mol. Biol. 287:265-76 (1999); andLorenzo, M. M. and Blasco, R. Biotechniques 24(2):308-13 (1998); each ofthese patents and publications are hereby incorporated by reference). Inone embodiment, alteration of polynucleotides and correspondingpolypeptides may be achieved by DNA shuffling. DNA shuffling involvesthe assembly of two or more DNA segments into a desired molecule byhomologous, or site-specific, recombination. In another embodiment,polynucleotides and corresponding polypeptides may be altered by beingsubjected to random mutagenesis by error-prone PCR, random nucleotideinsertion or other methods prior to recombination. In anotherembodiment, one or more components, motifs, sections, parts, domains,fragments, etc., of the polypeptide of the present invention may berecombined with one or more components, motifs, sections, parts,domains, fragments, etc. of one or more heterologous molecules. Inpreferred embodiments, the heterologous molecules are family members. Infurther preferred embodiments, the heterologous molecule is a growthfactor such as, for example, platelet-derived growth factor (PDGF),insulin-like growth factor (IGF-I), transforming growth factor(TGF)-alpha, epidermal growth factor (EGF), fibroblast growth factor(FGF), TGF-beta, bone morphogenetic protein (BMP)-2, BMP-4, BMP-5,BMP-6, BMP-7, activins A and B, decapentaplegic (dpp), 60A, OP-2,dorsalin, growth differentiation factors (GDFs), nodal, MIS,inhibin-alpha, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta5, andglial-derived neurotrophic factor (GDNF).

Other preferred fragments are biologically active fragments of thepolypeptide of the present invention. Biologically active fragments arethose exhibiting activity similar, but not necessarily identical, to anactivity of the polypeptide of the present invention. The biologicalactivity of the fragments may include an improved desired activity, or adecreased undesirable activity.

Additionally, this invention provides a method of screening compounds toidentify those which modulate the action of the polypeptide of thepresent invention. An example of such an assay comprises combining amammalian fibroblast cell, a the polypeptide of the present invention,the compound to be screened and ³[H] thymidine under cell cultureconditions where the fibroblast cell would normally proliferate. Acontrol assay may be performed in the absence of the compound to bescreened and compared to the amount of fibroblast proliferation in thepresence of the compound to determine if the compound stimulatesproliferation by determining the uptake of ³[H] thymidine in each case.The amount of fibroblast cell proliferation is measured by liquidscintillation chromatography which measures the incorporation of ³[H]thymidine. Both agonist and antagonist compounds may be identified bythis procedure.

In another method, a mammalian cell or membrane preparation expressing areceptor for a polypeptide of the present invention is incubated with alabeled polypeptide of the present invention in the presence of thecompound. The ability of the compound to enhance or block thisinteraction could then be measured. Alternatively, the response of aknown second messenger system following interaction of a compound to bescreened and the receptor is measured and the ability of the compound tobind to the receptor and elicit a second messenger response is measuredto determine if the compound is a potential agonist or antagonist. Suchsecond messenger systems include but are not limited to, cAMP guanylatecyclase, ion channels or phosphoinositide hydrolysis.

All of these above assays can be used as diagnostic or prognosticmarkers. The molecules discovered using these assays can be used totreat disease or to bring about a particular result in a patient (e.g.,blood vessel growth) by activating or inhibiting thepolypeptide/molecule. Moreover, the assays can discover agents which mayinhibit or enhance the production of the polypeptides of the inventionfrom suitably manipulated cells or tissues.

Therefore, the invention includes a method of identifying compoundswhich bind to a polypeptide of the invention comprising the steps of:(a) incubating a candidate binding compound with a polypeptide of thepresent invention; and (b) determining if binding has occurred.Moreover, the invention includes a method of identifyingagonists/antagonists comprising the steps of: (a) incubating a candidatecompound with a polypeptide of the present invention, (b) assaying abiological activity, and (b) determining if a biological activity of thepolypeptide has been altered.

Targeted Delivery

In another embodiment, the invention provides a method of deliveringcompositions to targeted cells expressing a receptor for a polypeptideof the invention, or cells expressing a cell bound form of a polypeptideof the invention.

As discussed herein, polypeptides or antibodies of the invention may beassociated with heterologous polypeptides, heterologous nucleic acids,toxins, or prodrugs via hydrophobic, hydrophilic, ionic and/or covalentinteractions. In one embodiment, the invention provides a method for thespecific delivery of compositions of the invention to cells byadministering polypeptides of the invention (including antibodies) thatare associated with heterologous polypeptides or nucleic acids. In oneexample, the invention provides a method for delivering a therapeuticprotein into the targeted cell. In another example, the inventionprovides a method for delivering a single stranded nucleic acid (e.g.,antisense or ribozymes) or double stranded nucleic acid (e.g., DNA thatcan integrate into the cell's genome or replicate episomally and thatcan be transcribed) into the targeted cell.

In another embodiment, the invention provides a method for the specificdestruction of cells (e.g., the destruction of tumor cells) byadministering polypeptides of the invention (e.g., polypeptides of theinvention or antibodies of the invention) in association with toxins orcytotoxic prodrugs.

By “toxin” is meant compounds that bind and activate endogenouscytotoxic effector systems, radioisotopes, holotoxins, modified toxins,catalytic subunits of toxins, or any molecules or enzymes not normallypresent in or on the surface of a cell that under defined conditionscause the cell's death. Toxins that may be used according to the methodsof the invention include, but are not limited to, radioisotopes known inthe art, compounds such as, for example, antibodies (or complementfixing containing portions thereof) that bind an inherent or inducedendogenous cytotoxic effector system, thymidine kinase, endonuclease,RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheriatoxin, saporin, momordin, gelonin, pokeweed antiviral protein,alpha-sarcin and cholera toxin. By “cytotoxic prodrug” is meant anon-toxic compound that is converted by an enzyme, normally present inthe cell, into a cytotoxic compound. Cytotoxic prodrugs that may be usedaccording to the methods of the invention include, but are not limitedto, glutamyl derivatives of benzoic acid mustard alkylating agent,phosphate derivatives of etoposide or mitomycin C, cytosine arabinoside,daunorubisin, and phenoxyacetamide derivatives of doxorubicin.

Drug Screening

Further contemplated is the use of the polypeptides of the presentinvention, or the polynucleotides encoding these polypeptides, to screenfor molecules which modify the activities of the polypeptides of thepresent invention. Such a method would include contacting thepolypeptide of the present invention with a selected compound(s)suspected of having antagonist or agonist activity, and assaying theactivity of these polypeptides following binding.

This invention is particularly useful for screening therapeuticcompounds by using the polypeptides of the present invention, or bindingfragments thereof, in any of a variety of drug screening techniques. Thepolypeptide or fragment employed in such a test may be affixed to asolid support, expressed on a cell surface, free in solution, or locatedintracellularly. One method of drug screening utilizes eukaryotic orprokaryotic host cells which are stably transformed with recombinantnucleic acids expressing the polypeptide or fragment. Drugs are screenedagainst such transformed cells in competitive binding assays. One maymeasure, for example, the formulation of complexes between the agentbeing tested and a polypeptide of the present invention.

Thus, the present invention provides methods of screening for drugs orany other agents which affect activities mediated by the polypeptides ofthe present invention. These methods comprise contacting such an agentwith a polypeptide of the present invention or a fragment thereof andassaying for the presence of a complex between the agent and thepolypeptide or a fragment thereof, by methods well known in the art. Insuch a competitive binding assay, the agents to screen are typicallylabeled. Following incubation, free agent is separated from that presentin bound form, and the amount of free or uncomplexed label is a measureof the ability of a particular agent to bind to the polypeptides of thepresent invention.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to the polypeptides ofthe present invention, and is described in great detail in EuropeanPatent Application 84/03564, published on Sep. 13, 1984, which isincorporated herein by reference herein. Briefly stated, large numbersof different small peptide test compounds are synthesized on a solidsubstrate, such as plastic pins or some other surface. The peptide testcompounds are reacted with polypeptides of the present invention andwashed. Bound polypeptides are then detected by methods well known inthe art. Purified polypeptides are coated directly onto plates for usein the aforementioned drug screening techniques. In addition,non-neutralizing antibodies may be used to capture the peptide andimmobilize it on the solid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding polypeptidesof the present invention specifically compete with a test compound forbinding to the polypeptides or fragments thereof. In this manner, theantibodies are used to detect the presence of any peptide which sharesone or more antigenic epitopes with a polypeptide of the invention.

Antisense And Ribozyme (Antagonists)

In specific embodiments, antagonists according to the present inventionare nucleic acids corresponding to the sequences contained in SEQ IDNO:X, or the complementary strand thereof, and/or to cDNA sequencescontained in cDNA ATCC Deposit No: Z identified for example, in Table 1Aand/or 1B. In one embodiment, antisense sequence is generatedinternally, by the organism, in another embodiment, the antisensesequence is separately administered (see, for example, O'Connor, J.,Neurochem. 56:560 (1991). Oligodeoxynucleotides as Antisense Inhibitorsof Gene Expression, CRC Press, Boca Raton, Fla. (1988). Antisensetechnology can be used to control gene expression through antisense DNAor RNA, or through triple-helix formation. Antisense techniques arediscussed for example, in Okano, J., Neurochem. 56:560 (1991);Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRCPress, Boca Raton, Fla. (1988). Triple helix formation is discussed in,for instance, Lee et al., Nucleic Acids Research 6:3073 (1979); Cooneyet al., Science 241:456 (1988); and Dervan et al., Science 251:1300(1991). The methods are based on binding of a polynucleotide to acomplementary DNA or RNA.

For example, the use of c-myc and c-myb antisense RNA constructs toinhibit the growth of the non-lymphocytic leukemia cell line HL-60 andother cell lines was previously described. (Wickstrom et al. (1988);Anfossi et al. (1989)). These experiments were performed in vitro byincubating cells with the oligoribonucleotide. A similar procedure forin vivo use is described in WO 91/15580. Briefly, a pair ofoligonucleotides for a given antisense RNA is produced as follows: Asequence complimentary to the first 15 bases of the open reading frameis flanked by an EcoRI site on the 5 end and a HindIII site on the 3end. Next, the pair of oligonucleotides is heated at 90° C. for oneminute and then annealed in 2× ligation buffer (20 mM TRIS HCl pH 7.5,10 mM MgCl2, 10MM dithiothreitol (DTT) and 0.2 mM ATP) and then ligatedto the EcoRI/Hind III site of the retroviral vector PMV7 (WO 91/15580).

For example, the 5′ coding portion of a polynucleotide that encodes thepolypeptide of the present invention may be used to design an antisenseRNA oligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription thereby preventing transcription and theproduction of the receptor. The antisense RNA oligonucleotide hybridizesto the mRNA in vivo and blocks translation of the mRNA molecule intoreceptor polypeptide.

In one embodiment, the antisense nucleic acid of the invention isproduced intracellularly by transcription from an exogenous sequence.For example, a vector or a portion thereof, is transcribed, producing anantisense nucleic acid (RNA) of the invention. Such a vector wouldcontain a sequence encoding the antisense nucleic acid. Such a vectorcan remain episomal or become chromosomally integrated, as long as itcan be transcribed to produce the desired antisense RNA. Such vectorscan be constructed by recombinant DNA technology methods standard in theart. Vectors can be plasmid, viral, or others known in the art, used forreplication and expression in vertebrate cells. Expression of thesequence encoding the polypeptide of the present invention or fragmentsthereof, can be by any promoter known in the art to act in vertebrate,preferably human cells. Such promoters can be inducible or constitutive.Such promoters include, but are not limited to, the SV40 early promoterregion (Bernoist and Chambon, Nature 29:304-310 (1981), the promotercontained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamotoet al., Cell 22:787-797 (1980), the herpes thymidine promoter (Wagner etal., Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445 (1981), the regulatorysequences of the metallothionein gene (Brinster, et al., Nature296:39-42 (1982)), etc.

The antisense nucleic acids of the invention comprise a sequencecomplementary to at least a portion of an RNA transcript of a gene ofthe present invention. However, absolute complementarity, althoughpreferred, is not required. A sequence “complementary to at least aportion of an RNA,” referred to herein, means a sequence havingsufficient complementarity to be able to hybridize with the RNA, forminga stable duplex; in the case of double stranded antisense nucleic acids,a single strand of the duplex DNA may thus be tested, or triplexformation may be assayed. The ability to hybridize will depend on boththe degree of complementarity and the length of the antisense nucleicacid. Generally, the larger the hybridizing nucleic acid, the more basemismatches with a RNA it may contain and still form a stable duplex (ortriplex as the case may be). One skilled in the art can ascertain atolerable degree of mismatch by use of standard procedures to determinethe melting point of the hybridized complex.

Oligonucleotides that are complementary to the 5′ end of the message,e.g., the 5′ untranslated sequence up to and including the AUGinitiation codon, should work most efficiently at inhibitingtranslation. However, sequences complementary to the 3′ untranslatedsequences of mRNAs have been shown to be effective at inhibitingtranslation of mRNAs as well. See generally, Wagner, R., 1994, Nature372:333-335. Thus, oligonucleotides complementary to either the 5′- or3′-non-translated, non-coding regions of polynucleotide sequencesdescribed herein could be used in an antisense approach to inhibittranslation of endogenous mRNA. Oligonucleotides complementary to the 5′untranslated region of the mRNA should include the complement of the AUGstart codon. Antisense oligonucleotides complementary to mRNA codingregions are less efficient inhibitors of translation but could be usedin accordance with the invention. Whether designed to hybridize to the5′-, 3′- or coding region of mRNA of the present invention, antisensenucleic acids should be at least six nucleotides in length, and arepreferably oligonucleotides ranging from 6 to about 50 nucleotides inlength. In specific aspects the oligonucleotide is at least 10nucleotides, at least 17 nucleotides, at least 25 nucleotides or atleast 50 nucleotides.

The polynucleotides of the invention can be DNA or RNA or chimericmixtures or derivatives or modified versions thereof, single-stranded ordouble-stranded. The oligonucleotide can be modified at the base moiety,sugar moiety, or phosphate backbone, for example, to improve stabilityof the molecule, hybridization, etc. The oligonucleotide may includeother appended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci.U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci.84:648-652; PCT Publication No. WO88/09810, published Dec. 15, 1988) orthe blood-brain barrier (see, e.g., PCT Publication No. WO89/10134,published Apr. 25, 1988), hybridization-triggered cleavage agents. (See,e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalatingagents. (See, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, theoligonucleotide may be conjugated to another molecule, e.g., a peptide,hybridization triggered cross-linking agent, transport agent,hybridization-triggered cleavage agent, etc.

The antisense oligonucleotide may comprise at least one modified basemoiety which is selected from the group including, but not limited to,5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine.

The antisense oligonucleotide may also comprise at least one modifiedsugar moiety selected from the group including, but not limited to,arabinose, 2-fluoroarabinose, xylulose, and hexose.

In yet another embodiment, the antisense oligonucleotide comprises atleast one modified phosphate backbone selected from the group including,but not limited to, a phosphorothioate, a phosphorodithioate, aphosphoramidothioate, a phosphoramidate, a phosphordiamidate, amethylphosphonate, an alkyl phosphotriester, and a formacetal or analogthereof.

In yet another embodiment, the antisense oligonucleotide is ana-anomeric oligonucleotide. An a-anomeric oligonucleotide forms specificdouble-stranded hybrids with complementary RNA in which, contrary to theusual b-units, the strands run parallel to each other (Gautier et al.,1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a2′-O-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res.15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBSLett. 215:327-330).

Polynucleotides of the invention may be synthesized by standard methodsknown in the art, e.g. by use of an automated DNA synthesizer (such asare commercially available from Biosearch, Applied Biosystems, etc.). Asexamples, phosphorothioate oligonucleotides may be synthesized by themethod of Stein et al. (1988, Nucl. Acids Res. 16:3209),methylphosphonate oligonucleotides can be prepared by use of controlledpore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci.U.S.A. 85:7448-7451), etc.

While antisense nucleotides complementary to the coding region sequencecould be used, those complementary to the transcribed untranslatedregion are most preferred.

Potential antagonists according to the invention also include catalyticRNA, or a ribozyme (See, e.g., PCT International Publication WO90/11364, published Oct. 4, 1990; Sarver et al, Science 247:1222-1225(1990). While ribozymes that cleave mRNA at site specific recognitionsequences can be used to destroy mRNAs, the use of hammerhead ribozymesis preferred. Hammerhead ribozymes cleave mRNAs at locations dictated byflanking regions that form complementary base pairs with the targetmRNA. The sole requirement is that the target mRNA have the followingsequence of two bases: 5′-UG-3′. The construction and production ofhammerhead ribozymes is well known in the art and is described morefully in Haseloff and Gerlach, Nature 334:585-591 (1988). There arenumerous potential hammerhead ribozyme cleavage sites within thenucleotide sequence of SEQ ID NO:X. Preferably, the ribozyme isengineered so that the cleavage recognition site is located near the 5′end of the mRNA; i.e., to increase efficiency and minimize theintracellular accumulation of non-functional mRNA transcripts.

As in the antisense approach, the ribozymes of the invention can becomposed of modified oligonucleotides (e.g., for improved stability,targeting, etc.) and should be delivered to cells which express in vivo.DNA constructs encoding the ribozyme may be introduced into the cell inthe same manner as described above for the introduction of antisenseencoding DNA. A preferred method of delivery involves using a DNAconstruct “encoding” the ribozyme under the control of a strongconstitutive promoter, such as, for example, pol III or pol II promoter,so that transfected cells will produce sufficient quantities of theribozyme to destroy endogenous messages and inhibit translation. Sinceribozymes unlike antisense molecules, are catalytic, a lowerintracellular concentration is required for efficiency.

Antagonist/agonist compounds may be employed to inhibit the cell growthand proliferation effects of the polypeptides of the present inventionon neoplastic cells and tissues, i.e. stimulation of angiogenesis oftumors, and, therefore, retard or prevent abnormal cellular growth andproliferation, for example, in tumor formation or growth.

The antagonist/agonist may also be employed to prevent hyper-vasculardiseases, and prevent the proliferation of epithelial lens cells afterextracapsular cataract surgery. Prevention of the mitogenic activity ofthe polypeptides of the present invention may also be desirous in casessuch as restenosis after balloon angioplasty.

The antagonist/agonist may also be employed to prevent the growth ofscar tissue during wound healing.

The antagonist/agonist may also be employed to treat the diseasesdescribed herein.

Thus, the invention provides a method of treating disorders or diseases,including but not limited to the disorders or diseases listed throughoutthis application, associated with overexpression of a polynucleotide ofthe present invention by administering to a patient (a) an antisensemolecule directed to the polynucleotide of the present invention, and/or(b) a ribozyme directed to the polynucleotide of the present invention.

Binding Peptides and Other Molecules

The invention also encompasses screening methods for identifyingpolypeptides and nonpolypeptides that bind polypeptides of theinvention, and the binding molecules identified thereby. These bindingmolecules are useful, for example, as agonists and antagonists of thepolypeptides of the invention. Such agonists and antagonists can beused, in accordance with the invention, in the therapeutic embodimentsdescribed in detail, below.

This method comprises the steps of:

-   -   a. contacting polypeptides of the invention with a plurality of        molecules; and    -   b. identifying a molecule that binds the polypeptides of the        invention.

The step of contacting the polypeptides of the invention with theplurality of molecules may be effected in a number of ways. For example,one may contemplate immobilizing the polypeptides on a solid support andbringing a solution of the plurality of molecules in contact with theimmobilized polypeptides. Such a procedure would be akin to an affinitychromatographic process, with the affinity matrix being comprised of theimmobilized polypeptides of the invention. The molecules having aselective affinity for the polypeptides can then be purified by affinityselection. The nature of the solid support, process for attachment ofthe polypeptides to the solid support, solvent, and conditions of theaffinity isolation or selection are largely conventional and well knownto those of ordinary skill in the art.

Alternatively, one may also separate a plurality of polypeptides intosubstantially separate fractions comprising a subset of or individualpolypeptides. For instance, one can separate the plurality ofpolypeptides by gel electrophoresis, column chromatography, or likemethod known to those of ordinary skill for the separation ofpolypeptides. The individual polypeptides can also be produced by atransformed host cell in such a way as to be expressed on or about itsouter surface (e.g., a recombinant phage). Individual isolates can thenbe “probed” by the polypeptides of the invention, optionally in thepresence of an inducer should one be required for expression, todetermine if any selective affinity interaction takes place between thepolypeptides and the individual clone. Prior to contacting thepolypeptides with each fraction comprising individual polypeptides, thepolypeptides could first be transferred to a solid support foradditional convenience. Such a solid support may simply be a piece offilter membrane, such as one made of nitrocellulose or nylon. In thismanner, positive clones could be identified from a collection oftransformed host cells of an expression library, which harbor a DNAconstruct encoding a polypeptide having a selective affinity forpolypeptides of the invention. Furthermore, the amino acid sequence ofthe polypeptide having a selective affinity for the polypeptides of theinvention can be determined directly by conventional means or the codingsequence of the DNA encoding the polypeptide can frequently bedetermined more conveniently. The primary sequence can then be deducedfrom the corresponding DNA sequence. If the amino acid sequence is to bedetermined from the polypeptide itself, one may use microsequencingtechniques. The sequencing technique may include mass spectroscopy.

In certain situations, it may be desirable to wash away any unboundpolypeptides from a mixture of the polypeptides of the invention and theplurality of polypeptides prior to attempting to determine or to detectthe presence of a selective affinity interaction. Such a wash step maybe particularly desirable when the polypeptides of the invention or theplurality of polypeptides are bound to a solid support.

The plurality of molecules provided according to this method may beprovided by way of diversity libraries, such as random or combinatorialpeptide or nonpeptide libraries which can be screened for molecules thatspecifically bind polypeptides of the invention. Many libraries areknown in the art that can be used, e.g., chemically synthesizedlibraries, recombinant (e.g., phage display libraries), and in vitrotranslation-based libraries. Examples of chemically synthesizedlibraries are described in Fodor et al., 1991, Science 251:767-773;Houghten et al., 1991, Nature 354:84-86; Lam et al., 1991, Nature354:82-84; Medynski, 1994, Bio/Technology 12:709-710; Gallop et al.,1994, J. Medicinal Chemistry 37(9):1233-1251; Ohlmeyer et al., 1993,Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl.Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA91:1614-1618; Salmon et al., 1993, Proc. Natl. Acad. Sci. USA90:11708-11712; PCT Publication No. WO 93/20242; and Brenner and Lerner,1992, Proc. Natl. Acad. Sci. USA 89:5381-5383.

Examples of phage display libraries are described in Scott and Smith,1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406;Christian, R. B., et al., 1992, J. Mol. Biol. 227:711-718); Lenstra,1992, J. Immunol. Meth. 152:149-157; Kay et al., 1993, Gene 128:59-65;and PCT Publication No. WO 94/18318 dated Aug. 18, 1994.

In vitro translation-based libraries include but are not limited tothose described in PCT Publication No. WO 91/05058 dated Apr. 18, 1991;and Mattheakis et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026.

By way of examples of nonpeptide libraries, a benzodiazepine library(see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712)can be adapted for use. Peptoid libraries (Simon et al., 1992, Proc.Natl. Acad. Sci. USA 89:9367-9371) can also be used. Another example ofa library that can be used, in which the amide functionalities inpeptides have been permethylated to generate a chemically transformedcombinatorial library, is described by Ostresh et al. (1994, Proc. Natl.Acad. Sci. USA 91:11138-11142).

The variety of non-peptide libraries that are useful in the presentinvention is great. For example, Ecker and Crooke, 1995, Bio/Technology13:351-360 list benzodiazepines, hydantoins, piperazinediones,biphenyls, sugar analogs, beta-mercaptoketones, arylacetic acids,acylpiperidines, benzopyrans, cubanes, xanthines, aminimides, andoxazolones as among the chemical species that form the basis of variouslibraries.

Non-peptide libraries can be classified broadly into two types:decorated monomers and oligomers. Decorated monomer libraries employ arelatively simple scaffold structure upon which a variety functionalgroups is added. Often the scaffold will be a molecule with a knownuseful pharmacological activity. For example, the scaffold might be thebenzodiazepine structure.

Non-peptide oligomer libraries utilize a large number of monomers thatare assembled together in ways that create new shapes that depend on theorder of the monomers. Among the monomer units that have been used arecarbamates, pyrrolinones, and morpholinos. Peptoids, peptide-likeoligomers in which the side chain is attached to the alpha amino grouprather than the alpha carbon, form the basis of another version ofnon-peptide oligomer libraries. The first non-peptide oligomer librariesutilized a single type of monomer and thus contained a repeatingbackbone. Recent libraries have utilized more than one monomer, givingthe libraries added flexibility.

Screening the libraries can be accomplished by any of a variety ofcommonly known methods. See, e.g., the following references, whichdisclose screening of peptide libraries: Parmley and Smith, 1989, Adv.Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390;Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992,Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992,Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Pat. No.5,096,815, U.S. Pat. No. 5,223,409, and U.S. Pat. No. 5,198,346, all toLadner et al.; Rebar and Pabo, 1993, Science 263:671-673; and CTPublication No. WO 94/18318.

In a specific embodiment, screening to identify a molecule that bindspolypeptides of the invention can be carried out by contacting thelibrary members with polypeptides of the invention immobilized on asolid phase and harvesting those library members that bind to thepolypeptides of the invention. Examples of such screening methods,termed “panning” techniques are described by way of example in Parmleyand Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques13:422-427; PCT Publication No. WO 94/18318; and in references citedherein.

In another embodiment, the two-hybrid system for selecting interactingproteins in yeast (Fields and Song, 1989, Nature 340:245-246; Chien etal., 1991, Proc. Natl. Acad. Sci. USA 88:9578-9582) can be used toidentify molecules that specifically bind to polypeptides of theinvention.

Where the binding molecule is a polypeptide, the polypeptide can beconveniently selected from any peptide library, including random peptidelibraries, combinatorial peptide libraries, or biased peptide libraries.The term “biased” is used herein to mean that the method of generatingthe library is manipulated so as to restrict one or more parameters thatgovern the diversity of the resulting collection of molecules, in thiscase peptides.

Thus, a truly random peptide library would generate a collection ofpeptides in which the probability of finding a particular amino acid ata given position of the peptide is the same for all 20 amino acids. Abias can be introduced into the library, however, by specifying, forexample, that a lysine occur every fifth amino acid or that positions 4,8, and 9 of a decapeptide library be fixed to include only arginine.Clearly, many types of biases can be contemplated, and the presentinvention is not restricted to any particular bias. Furthermore, thepresent invention contemplates specific types of peptide libraries, suchas phage displayed peptide libraries and those that utilize a DNAconstruct comprising a lambda phage vector with a DNA insert.

As mentioned above, in the case of a binding molecule that is apolypeptide, the polypeptide may have about 6 to less than about 60amino acid residues, preferably about 6 to about 10 amino acid residues,and most preferably, about 6 to about 22 amino acids. In anotherembodiment, a binding polypeptide has in the range of 15-100 aminoacids, or 20-50 amino acids.

The selected binding polypeptide can be obtained by chemical synthesisor recombinant expression.

Other Activities

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention, as a result of the ability to stimulate vascular endothelialcell growth, may be employed in treatment for stimulatingre-vascularization of ischemic tissues due to various disease conditionssuch as thrombosis, arteriosclerosis, and other cardiovascularconditions. The polypeptide, polynucleotide, agonist, or antagonist ofthe present invention may also be employed to stimulate angiogenesis andlimb regeneration, as discussed above.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed for treating wounds due to injuries,burns, post-operative tissue repair, and ulcers since they are mitogenicto various cells of different origins, such as fibroblast cells andskeletal muscle cells, and therefore, facilitate the repair orreplacement of damaged or diseased tissue.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed stimulate neuronal growth and to treatand prevent neuronal damage which occurs in certain neuronal disordersor neuro-degenerative conditions such as Alzheimer's disease,Parkinson's disease, and AIDS-related complex. A polypeptide,polynucleotide, agonist, or antagonist of the present invention may havethe ability to stimulate chondrocyte growth, therefore, they may beemployed to enhance bone and periodontal regeneration and aid in tissuetransplants or bone grafts.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may be also be employed to prevent skin aging due to sunburnby stimulating keratinocyte growth.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed for preventing hair loss, since FGFfamily members activate hair-forming cells and promotes melanocytegrowth. Along the same lines, a polypeptide, polynucleotide, agonist, orantagonist of the present invention may be employed to stimulate growthand differentiation of hematopoietic cells and bone marrow cells whenused in combination with other cytokines.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be employed to maintain organs before transplantationor for supporting cell culture of primary tissues. A polypeptide,polynucleotide, agonist, or antagonist of the present invention may alsobe employed for inducing tissue of mesodermal origin to differentiate inearly embryos.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also increase or decrease the differentiation orproliferation of embryonic stem cells, besides, as discussed above,hematopoietic lineage.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be used to modulate mammalian characteristics, suchas body height, weight, hair color, eye color, skin, percentage ofadipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery).Similarly, a polypeptide, polynucleotide, agonist, or antagonist of thepresent invention may be used to modulate mammalian metabolism affectingcatabolism, anabolism, processing, utilization, and storage of energy.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may be used to change a mammal's mental state or physicalstate by influencing biorhythms, caricadic rhythms, depression(including depressive disorders), tendency for violence, tolerance forpain, reproductive capabilities (preferably by Activin or Inhibin-likeactivity), hormonal or endocrine levels, appetite, libido, memory,stress, or other cognitive qualities.

A polypeptide, polynucleotide, agonist, or antagonist of the presentinvention may also be used as a food additive or preservative, such asto increase or decrease storage capabilities, fat content, lipid,protein, carbohydrate, vitamins, minerals, cofactors or othernutritional components.

The above-recited applications have uses in a wide variety of hosts.Such hosts include, but are not limited to, human, murine, rabbit, goat,guinea pig, camel, horse, mouse, rat, hamster, pig, micro-pig, chicken,goat, cow, sheep, dog, cat, non-human primate, and human. In specificembodiments, the host is a mouse, rabbit, goat, guinea pig, chicken,rat, hamster, pig, sheep, dog or cat. In preferred embodiments, the hostis a mammal. In most preferred embodiments, the host is a human.

Other Preferred Embodiments

Other preferred embodiments of the claimed invention include an isolatednucleic acid molecule comprising a nucleotide sequence which is at least95% identical to a sequence of at least about 50 contiguous nucleotidesin the nucleotide sequence of SEQ ID NO:X or the complementary strandthereto, the nucleotide sequence as defined in column 5 of Table 1B.1 orcolumns 8 and 9 of Table 2 or the complementary strand thereto, and/orcDNA contained in ATCC Deposit No: Z.

Also preferred is a nucleic acid molecule wherein said sequence ofcontiguous nucleotides is included in the nucleotide sequence of theportion of SEQ ID NO:X as defined in column 5, “ORF (From-To)”, in Table1B.1.

Also preferred is a nucleic acid molecule wherein said sequence ofcontiguous nucleotides is included in the nucleotide sequence of theportion of SEQ ID NO:X as defined in columns 8 and 9, “NT From” and “NTTo” respectively, in Table 2.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a sequence of atleast about 150 contiguous nucleotides in the nucleotide sequence of SEQID NO:X or the complementary strand thereto, the nucleotide sequence asdefined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or thecomplementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z.

Further preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a sequence of atleast about 500 contiguous nucleotides in the nucleotide sequence of SEQID NO:X or the complementary strand thereto, the nucleotide sequence asdefined in column 5 of Table 1B.1 or columns 8 and 9 of Table 2 or thecomplementary strand thereto, and/or cDNA contained in ATCC Deposit No:Z.

A further preferred embodiment is a nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to the nucleotidesequence of the portion of SEQ ID NO:X defined in column 5, “ORF(From-To)”, in Table 1B.1.

A further preferred embodiment is a nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to the nucleotidesequence of the portion of SEQ ID NO:X defined in columns 8 and 9, “NTFrom” and “NT To”, respectively, in Table 2.

A further preferred embodiment is an isolated nucleic acid moleculecomprising a nucleotide sequence which is at least 95% identical to thecomplete nucleotide sequence of SEQ ID NO:X or the complementary strandthereto, the nucleotide sequence as defined in column 5 of Table 1B.1 orcolumns 8 and 9 of Table 2 or the complementary strand thereto, and/orcDNA contained in ATCC Deposit No: Z.

Also preferred is an isolated nucleic acid molecule which hybridizesunder stringent hybridization conditions to a nucleic acid moleculecomprising a nucleotide sequence of SEQ ID NO:X or the complementarystrand thereto, the nucleotide sequence as defined in column 5 of Table1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto,and/or cDNA contained in ATCC Deposit No: Z, wherein said nucleic acidmolecule which hybridizes does not hybridize under stringenthybridization conditions to a nucleic acid molecule having a nucleotidesequence consisting of only A residues or of only T residues.

Also preferred is a composition of matter comprising a DNA moleculewhich comprises the cDNA contained in ATCC Deposit No: Z.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a sequence of atleast 50 contiguous nucleotides of the cDNA sequence contained in ATCCDeposit No: Z.

Also preferred is an isolated nucleic acid molecule, wherein saidsequence of at least 50 contiguous nucleotides is included in thenucleotide sequence of an open reading frame sequence encoded by cDNAcontained in ATCC Deposit No: Z.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to sequence of atleast 150 contiguous nucleotides in the nucleotide sequence encoded bycDNA contained in ATCC Deposit No: Z.

A further preferred embodiment is an isolated nucleic acid moleculecomprising a nucleotide sequence which is at least 95% identical tosequence of at least 500 contiguous nucleotides in the nucleotidesequence encoded by cDNA contained in ATCC Deposit No: Z.

A further preferred embodiment is an isolated nucleic acid moleculecomprising a nucleotide sequence which is at least 95% identical to thecomplete nucleotide sequence encoded by cDNA contained in ATCC DepositNo: Z.

A further preferred embodiment is a method for detecting in a biologicalsample a nucleic acid molecule comprising a nucleotide sequence which isat least 95% identical to a sequence of at least 50 contiguousnucleotides in a sequence selected from the group consisting of: anucleotide sequence of SEQ ID NO:X or the complementary strand thereto;the nucleotide sequence as defined in column 5 of Table 1B. 1 or columns8 and 9 of Table 2 or the complementary strand thereto; and a nucleotidesequence encoded by cDNA contained in ATCC Deposit No: Z; which methodcomprises a step of comparing a nucleotide sequence of at least onenucleic acid molecule in said sample with a sequence selected from saidgroup and determining whether the sequence of said nucleic acid moleculein said sample is at least 95% identical to said selected sequence.

Also preferred is the above method wherein said step of comparingsequences comprises determining the extent of nucleic acid hybridizationbetween nucleic acid molecules in said sample and a nucleic acidmolecule comprising said sequence selected from said group. Similarly,also preferred is the above method wherein said step of comparingsequences is performed by comparing the nucleotide sequence determinedfrom a nucleic acid molecule in said sample with said sequence selectedfrom said group. The nucleic acid molecules can comprise DNA moleculesor RNA molecules.

A further preferred embodiment is a method for identifying the species,tissue or cell type of a biological sample which method comprises a stepof detecting nucleic acid molecules in said sample, if any, comprising anucleotide sequence that is at least 95% identical to a sequence of atleast 50 contiguous nucleotides in a sequence selected from the groupconsisting of: a nucleotide sequence of SEQ ID NO:X or the complementarystrand thereto; the nucleotide sequence as defined in column 5 of Table1B.1 or columns 8 and 9 of Table 2 or the complementary strand thereto;and a nucleotide sequence of the cDNA contained in ATCC Deposit No: Z.

The method for identifying the species, tissue or cell type of abiological sample can comprise a step of detecting nucleic acidmolecules comprising a nucleotide sequence in a panel of at least twonucleotide sequences, wherein at least one sequence in said panel is atleast 95% identical to a sequence of at least 50 contiguous nucleotidesin a sequence selected from said group.

Also preferred is a method for diagnosing in a subject a pathologicalcondition associated with abnormal structure or expression of anucleotide sequence of SEQ ID NO:X or the complementary strand thereto;the nucleotide sequence as defined in column 5 of Table 1B.1 or columns8 and 9 of Table 2 or the complementary strand thereto; or the cDNAcontained in ATCC Deposit No: Z which encodes a protein, wherein themethod comprises a step of detecting in a biological sample obtainedfrom said subject nucleic acid molecules, if any, comprising anucleotide sequence that is at least 95% identical to a sequence of atleast 50 contiguous nucleotides in a sequence selected from the groupconsisting of: a nucleotide sequence of SEQ ID NO:X or the complementarystrand thereto; the nucleotide sequence as defined in column 5 of Table1B. 1 or columns 8 and 9 of Table 2 or the complementary strand thereto;and a nucleotide sequence of cDNA contained in ATCC Deposit No: Z.

The method for diagnosing a pathological condition can comprise a stepof detecting nucleic acid molecules comprising a nucleotide sequence ina panel of at least two nucleotide sequences, wherein at least onesequence in said panel is at least 95% identical to a sequence of atleast 50 contiguous nucleotides in a sequence selected from said group.

Also preferred is a composition of matter comprising isolated nucleicacid molecules wherein the nucleotide sequences of said nucleic acidmolecules comprise a panel of at least two nucleotide sequences, whereinat least one sequence in said panel is at least 95% identical to asequence of at least 50 contiguous nucleotides in a sequence selectedfrom the group consisting of: a nucleotide sequence of SEQ ID NO:X orthe complementary strand thereto; the nucleotide sequence as defined incolumn 5 of Table 1B.1 or columns 8 and 9 of Table 2 or thecomplementary strand thereto; and a nucleotide sequence encoded by cDNAcontained in ATCC Deposit No: Z. The nucleic acid molecules can compriseDNA molecules or RNA molecules.

Also preferred is a composition of matter comprising isolated nucleicacid molecules wherein the nucleotide sequences of said nucleic acidmolecules comprise a DNA microarray or “chip” of at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 150, 200, 250, 300, 500,1000, 2000, 3000, or 4000 nucleotide sequences, wherein at least onesequence in said DNA microarray or “chip” is at least 95% identical to asequence of at least 50 contiguous nucleotides in a sequence selectedfrom the group consisting of: a nucleotide sequence of SEQ ID NO:Xwherein X is any integer as defined in Table 1A and/or 1B; and anucleotide sequence encoded by a human cDNA clone identified by a cDNA“Clone ID” in Table 1A and/or 1B.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 90% identical to a sequence of at least about 10contiguous amino acids in the polypeptide sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained inATCC Deposit No: Z.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 30contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained inATCC Deposit No: Z.

Further preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 100contiguous amino acids in the amino acid sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or a polypeptide encoded by cDNA contained inATCC Deposit No: Z.

Further preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to the complete amino acid sequence ofSEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or the complementarystrand thereto; the polypeptide encoded by the nucleotide sequence asdefined in columns 8 and 9 of Table 2; and/or a polypeptide encoded bycDNA contained in ATCC Deposit No: Z.

Further preferred is an isolated polypeptide comprising an amino acidsequence at least 90% identical to a sequence of at least about 10contiguous amino acids in the complete amino acid sequence of apolypeptide encoded by contained in ATCC Deposit No: Z

Also preferred is a polypeptide wherein said sequence of contiguousamino acids is included in the amino acid sequence of a portion of saidpolypeptide encoded by cDNA contained in ATCC Deposit No: Z; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and/or the polypeptide sequence of SEQ ID NO:Y.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 30contiguous amino acids in the amino acid sequence of a polypeptideencoded by the cDNA contained in ATCC Deposit No: Z.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to a sequence of at least about 100contiguous amino acids in the amino acid sequence of a polypeptideencoded by cDNA contained in ATCC Deposit No: Z.

Also preferred is an isolated polypeptide comprising an amino acidsequence at least 95% identical to the amino acid sequence of apolypeptide encoded by the cDNA contained in ATCC Deposit No: Z.

Further preferred is an isolated antibody which binds specifically to apolypeptide comprising an amino acid sequence that is at least 90%identical to a sequence of at least 10 contiguous amino acids in asequence selected from the group consisting of: a polypeptide sequenceof SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or thecomplementary strand thereto; the polypeptide encoded by the nucleotidesequence as defined in columns 8 and 9 of Table 2; and a polypeptideencoded by the cDNA contained in ATCC Deposit No: Z.

Further preferred is a method for detecting in a biological sample apolypeptide comprising an amino acid sequence which is at least 90%identical to a sequence of at least 10 contiguous amino acids in asequence selected from the group consisting of: a polypeptide sequenceof SEQ ID NO:Y; a polypeptide encoded by SEQ ID NO:X or thecomplementary strand thereto; the polypeptide encoded by the nucleotidesequence as defined in columns 8 and 9 of Table 2; and a polypeptideencoded by the cDNA contained in ATCC Deposit No: Z; which methodcomprises a step of comparing an amino acid sequence of at least onepolypeptide molecule in said sample with a sequence selected from saidgroup and determining whether the sequence of said polypeptide moleculein said sample is at least 90% identical to said sequence of at least 10contiguous amino acids.

Also preferred is the above method wherein said step of comparing anamino acid sequence of at least one polypeptide molecule in said samplewith a sequence selected from said group comprises determining theextent of specific binding of polypeptides in said sample to an antibodywhich binds specifically to a polypeptide comprising an amino acidsequence that is at least 90% identical to a sequence of at least 10contiguous amino acids in a sequence selected from the group consistingof: a polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQID NO:X or the complementary strand thereto; the polypeptide encoded bythe nucleotide sequence as defined in columns 8 and 9 of Table 2; and apolypeptide encoded by the cDNA contained in ATCC Deposit No: Z.

Also preferred is the above method wherein said step of comparingsequences is performed by comparing the amino acid sequence determinedfrom a polypeptide molecule in said sample with said sequence selectedfrom said group.

Also preferred is a method for identifying the species, tissue or celltype of a biological sample which method comprises a step of detectingpolypeptide molecules in said sample, if any, comprising an amino acidsequence that is at least 90% identical to a sequence of at least 10contiguous amino acids in a sequence selected from the group consistingof: polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ IDNO:X or the complementary strand thereto; the polypeptide encoded by thenucleotide sequence as defined in columns 8 and 9 of Table 2; and apolypeptide encoded by the cDNA contained in ATCC Deposit No: Z.

Also preferred is the above method for identifying the species, tissueor cell type of a biological sample, which method comprises a step ofdetecting polypeptide molecules comprising an amino acid sequence in apanel of at least two amino acid sequences, wherein at least onesequence in said panel is at least 90% identical to a sequence of atleast 10 contiguous amino acids in a sequence selected from the abovegroup.

Also preferred is a method for diagnosing in a subject a pathologicalcondition associated with abnormal structure or expression of a nucleicacid sequence identified in Table 1A, 1B or Table 2 encoding apolypeptide, which method comprises a step of detecting in a biologicalsample obtained from said subject polypeptide molecules comprising anamino acid sequence in a panel of at least two amino acid sequences,wherein at least one sequence in said panel is at least 90% identical toa sequence of at least 10 contiguous amino acids in a sequence selectedfrom the group consisting of: polypeptide sequence of SEQ ID NO:Y; apolypeptide encoded by SEQ ID NO:X or the complementary strand thereto;the polypeptide encoded by the nucleotide sequence as defined in columns8 and 9 of Table 2; and a polypeptide encoded by the cDNA contained inATCC Deposit No: Z.

In any of these methods, the step of detecting said polypeptidemolecules includes using an antibody.

Also preferred is an isolated nucleic acid molecule comprising anucleotide sequence which is at least 95% identical to a nucleotidesequence encoding a polypeptide wherein said polypeptide comprises anamino acid sequence that is at least 90% identical to a sequence of atleast 10 contiguous amino acids in a sequence selected from the groupconsisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptideencoded by SEQ ID NO:X or the complementary strand thereto; thepolypeptide encoded by the nucleotide sequence as defined in columns 8and 9 of Table 2; and a polypeptide encoded by the cDNA contained inATCC Deposit No: Z.

Also preferred is an isolated nucleic acid molecule, wherein saidnucleotide sequence encoding a polypeptide has been optimized forexpression of said polypeptide in a prokaryotic host.

Also preferred is a polypeptide molecule, wherein said polypeptidecomprises an amino acid sequence selected from the group consisting of:polypeptide sequence of SEQ ID NO:Y; a polypeptide encoded by SEQ IDNO:X or the complementary strand thereto; the polypeptide encoded by thenucleotide sequence as defined in columns 8 and 9 of Table 2; and apolypeptide encoded by the cDNA contained in ATCC Deposit No: Z.

Further preferred is a method of making a recombinant vector comprisinginserting any of the above isolated nucleic acid molecule into a vector.Also preferred is the recombinant vector produced by this method. Alsopreferred is a method of making a recombinant host cell comprisingintroducing the vector into a host cell, as well as the recombinant hostcell produced by this method.

Also preferred is a method of making an isolated polypeptide comprisingculturing this recombinant host cell under conditions such that saidpolypeptide is expressed and recovering said polypeptide. Also preferredis this method of making an isolated polypeptide, wherein saidrecombinant host cell is a eukaryotic cell and said polypeptide is ahuman protein comprising an amino acid sequence selected from the groupconsisting of: polypeptide sequence of SEQ ID NO:Y; a polypeptideencoded by SEQ ID NO:X or the complementary strand thereto; thepolypeptide encoded by the nucleotide sequence as defined in columns 8and 9 of Table 2; and a polypeptide encoded by the cDNA contained inATCC Deposit No: Z. The isolated polypeptide produced by this method isalso preferred.

Also preferred is a method of treatment of an individual in need of anincreased level of a protein activity, which method comprisesadministering to such an individual a Therapeutic comprising an amountof an isolated polypeptide, polynucleotide, immunogenic fragment oranalogue thereof, binding agent, antibody, or antigen binding fragmentof the claimed invention effective to increase the level of said proteinactivity in said individual.

Also preferred is a method of treatment of an individual in need of adecreased level of a protein activity, which method comprisedadministering to such an individual a Therapeutic comprising an amountof an isolated polypeptide, polynucleotide, immunogenic fragment oranalogue thereof, binding agent, antibody, or antigen binding fragmentof the claimed invention effective to decrease the level of said proteinactivity in said individual.

Also preferred is a method of treatment of an individual in need of aspecific delivery of toxic compositions to diseased cells (e.g., tumors,leukemias or lymphomas), which method comprises administering to such anindividual a Therapeutic comprising an amount of an isolated polypeptideof the invention, including, but not limited to a binding agent, orantibody of the claimed invention that are associated with toxin orcytotoxic prodrugs.

Having generally described the invention, the same will be more readilyunderstood by reference to the following examples, which are provided byway of illustration and are not intended as limiting.

Description of Table 6

Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCCdesignation numbers of deposits made with the ATCC in connection withthe present application. These deposits were made in addition to thosedescribed in the Table 1A. TABLE 6 ATCC Deposits Deposit Date ATCCDesignation Number LP01, LP02, LP03, LP04, May-20-97 209059, 209060,209061, LP05, LP06, LP07, LP08, 209062, 209063, 209064, LP09, LP10,LP11, 209065, 209066, 209067, 209068, 209069 LP12 Jan-12-98 209579 LP13Jan-12-98 209578 LP14 Jul-16-98 203067 LP15 Jul-16-98 203068 LP16Feb-1-99 203609 LP17 Feb-1-99 203610 LP20 Nov-17-98 203485 LP21Jun-18-99 PTA-252 LP22 Jun-18-99 PTA-253 LP23 Dec-22-99 PTA-1081

EXAMPLES Example 1 Isolation of a Selected cDNA Clone from the DepositedSample

Each ATCC Deposit No: Z is contained in a plasmid vector. Table 7identifies the vectors used to construct the cDNA library from whicheach clone was isolated. In many cases, the vector used to construct thelibrary is a phage vector from which a plasmid has been excised. Thefollowing correlates the related plasmid for each phage vector used inconstructing the cDNA library. For example, where a particular clone isidentified in Table 7 as being isolated in the vector “Lambda Zap,” thecorresponding deposited clone is in “pBluescript.” Vector Used toConstruct Library Corresponding Deposited Plasmid Lambda Zap pBluescript(pBS) Uni-Zap XR pBluescript (pBS) Zap Express pBK lafmid BA plafmid BApSport1 pSport1 pCMVSport 2.0 pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0pCR ® 2.1 pCR ® 2.1

Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636), Uni-Zap XR(U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Pat. Nos.5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al.,Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees, M. A. and Short, J.M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees, M. A. etal., Strategies 5:58-61 (1992)) are commercially available fromStratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla,Calif., 92037. pBS contains an ampicillin resistance gene and pBKcontains a neomycin resistance gene. Both can be transformed into E.coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4forms SK+, SK−, KS+ and KS. The S and K refers to the orientation of thepolylinker to the T7 and T3 primer sequences which flank the polylinkerregion (“S” is for SacI and “K” is for KpnI which are the first sites oneach respective end of the linker). “+” or “−” refer to the orientationof the f1 origin of replication (“ori”), such that in one orientation,single stranded rescue initiated from the f1 ori generates sense strandDNA and in the other, antisense.

Vectors pSport1, pCMVSport 2.0 and pCMVSport 3.0, were obtained fromLife Technologies, Inc., P.O. Box 6009, Gaithersburg, Md. 20897. AllSport vectors contain an ampicillin resistance gene and may betransformed into E. coli strain DH10B, also available from LifeTechnologies. (See, for instance, Gruber, C. E., et al., Focus 15:59(1993)). Vector lafmid BA (Bento Soares, Columbia University, NY)contains an ampicillin resistance gene and can be transformed into E.coli strain XL-1 Blue. Vector pCR®2.1, which is available fromInvitrogen, 1600 Faraday Avenue, Carlsbad, Calif. 92008, contains anampicillin resistance gene and may be transformed into E. coli strainDH10B, available from Life Technologies. (See, for instance, Clark, J.M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al.,Bio/Technology 9: (1991)). Preferably, a polynucleotide of the presentinvention does not comprise the phage vector sequences identified forthe particular clone in Table 7, as well as the corresponding plasmidvector sequences designated above.

The deposited material in the sample assigned the ATCC Deposit Numbercited by reference to Tables 1, 2, 6 and 7 for any given cDNA clone alsomay contain one or more additional plasmids, each comprising a cDNAclone different from that given clone. Thus, deposits sharing the sameATCC Deposit Number contain at least a plasmid for each ATCC Deposit No:Z. TABLE 7 ATCC Libraries owned by Catalog Catalog Description VectorDeposit HUKA HUKB HUKC HUKD Human Uterine Cancer Lambda ZAP II LP01 HUKEHUKF HUKG HCNA HCNB Human Colon Lambda Zap II LP01 HFFA Human FetalBrain, random Lambda Zap II LP01 primed HTWA Resting T-Cell Lambda ZAPII LP01 HBQA Early Stage Human Brain, Lambda ZAP II LP01 random primedHLMB HLMF HLMG HLMH breast lymph node CDNA Lambda ZAP II LP01 HLMI HLMJHLMM HLMN library HCQA HCQB human colon cancer Lamda ZAP II LP01 HMEAHMEC HMED Human Microvascular Lambda ZAP II LP01 HMEE HMEF HMEG HMEIEndothelial Cells, fract. A HMEJ HMEK HMEL HUSA HUSC Human UmbilicalVein Lambda ZAP II LP01 Endothelial Cells, fract. A HLQA HLQBHepatocellular Tumor Lambda ZAP II LP01 HHGA HHGB HHGC HHGDHemangiopericytoma Lambda ZAP II LP01 HSDM Human Striatum Depression,Lambda ZAP II LP01 re-rescue HUSH H Umbilical Vein Endothelial LambdaZAP II LP01 Cells, frac A, re-excision HSGS Salivary gland, subtractedLambda ZAP II LP01 HFXA HFXB HFXC HFXD Brain frontal cortex Lambda ZAPII LP01 HFXE HFXF HFXG HFXH HPQA HPQB HPQC PERM TF274 Lambda ZAP II LP01HFXJ HFXK Brain Frontal Cortex, re- Lambda ZAP II LP01 excision HCWAHCWB HCWC CD34 positive cells (Cord ZAP Express LP02 HCWD HCWE HCWFBlood) HCWG HCWH HCWI HCWJ HCWK HCUA HCUB HCUC CD34 depleted Buffy CoatZAP Express LP02 (Cord Blood) HRSM A-14 cell line ZAP Express LP02 HRSAA1-CELL LINE ZAP Express LP02 HCUD HCUE HCUF HCUG CD34 depleted BuffyCoat ZAP Express LP02 HCUH HCUI (Cord Blood), re-excision HBXE HBXF HBXGH. Whole Brain #2, re- ZAP Express LP02 excision HRLM L8 cell line ZAPExpress LP02 HBXA HBXB HBXC HBXD Human Whole Brain #2 - ZAP Express LP02Oligo dT >1.5 Kb HUDA HUDB HUDC Testes ZAP Express LP02 HHTM HHTN HHTOH. hypothalamus, frac A; re- ZAP Express LP02 excision HHTL H.hypothalamus, frac A ZAP Express LP02 HASA HASD Human Adult SpleenUni-ZAP XR LP03 HFKC HFKD HFKE HFKF Human Fetal Kidney Uni-ZAP XR LP03HFKG HE8A HE8B HE8C HE8D Human 8 Week Whole Uni-ZAP XR LP03 HE8E HE8FHE8M HE8N Embryo HGBA HGBD HGBE HGBF Human Gall Bladder Uni-ZAP XR LP03HGBG HGBH HGBI HLHA HLHB HLHC HLHD Human Fetal Lung III Uni-ZAP XR LP03HLHE HLHF HLHG HLHH HLHQ HPMA HPMB HPMC HPMD Human Placenta Uni-ZAP XRLP03 HPME HPMF HPMG HPMH HPRA HPRB HPRC HPRD Human Prostate Uni-ZAP XRLP03 HSIA HSIC HSID HSIE Human Adult Small Intestine Uni-ZAP XR LP03HTEA HTEB HTEC HTED Human Testes Uni-ZAP XR LP03 HTEE HTEF HTEG HTEHHTEI HTEJ HTEK HTPA HTPB HTPC HTPD Human Pancreas Tumor Uni-ZAP XR LP03HTPE HTTA HTTB HTTC HTTD Human Testes Tumor Uni-ZAP XR LP03 HTTE HTTFHAPA HAPB HAPC HAPM Human Adult Pulmonary Uni-ZAP XR LP03 HETA HETB HETCHETD Human Endometrial Tumor Uni-ZAP XR LP03 HETE HETF HETG HETH HETIHHFB HHFC HHFD HHFE Human Fetal Heart Uni-ZAP XR LP03 HHFF HHFG HHFHHHFI HHPB HHPC HHPD HHPE Human Hippocampus Uni-ZAP XR LP03 HHPF HHPGHHPH HCE1 HCE2 HCE3 HCE4 Human Cerebellum Uni-ZAP XR LP03 HCE5 HCEB HCECHCED HCEE HCEF HCEG HUVB HUVC HUVD HUVE Human Umbilical Vein, Uni-ZAP XRLP03 Endo. remake HSTA HSTB HSTC HSTD Human Skin Tumor Uni-ZAP XR LP03HTAA HTAB HTAC HTAD Human Activated T-Cells Uni-ZAP XR LP03 HTAE HFEAHFEB HFEC Human Fetal Epithelium Uni-ZAP XR LP03 (Skin) HJPA HJPB HJPCHJPD HUMAN JURKAT Uni-ZAP XR LP03 MEMBRANE BOUND POLYSOMES HESA Humanepithelioid sarcoma Uni-Zap XR LP03 HLTA HLTB HLTC HLTD Human T-CellLymphoma Uni-ZAP XR LP03 HLTE HLTF HFTA HFTB HFTC HFTD Human Fetal DuraMater Uni-ZAP XR LP03 HRDA HRDB HRDC HRDD Human Rhabdomyosarcoma Uni-ZAPXR LP03 HRDE HRDF HCAA HCAB HCAC Cem cells cyclohexamide Uni-ZAP XR LP03treated HRGA HRGB HRGC HRGD Raji Cells, cyclohexamide Uni-ZAP XR LP03treated HSUA HSUB HSUC HSUM Supt Cells, cyclohexamide Uni-ZAP XR LP03treated HT4A HT4C HT4D Activated T-Cells, 12 hrs. Uni-ZAP XR LP03 HE9AHE9B HE9C HE9D Nine Week Old Early Stage Uni-ZAP XR LP03 HE9E HE9F HE9GHE9H Human HE9M HE9N HATA HATB HATC HATD Human Adrenal Gland TumorUni-ZAP XR LP03 HATE HT5A Activated T-Cells, 24 hrs. Uni-ZAP XR LP03HFGA HFGM Human Fetal Brain Uni-ZAP XR LP03 HNEA HNEB HNEC HNED HumanNeutrophil Uni-ZAP XR LP03 HNEE HBGB HBGD Human Primary Breast Uni-ZAPXR LP03 Cancer HBNA HBNB Human Normal Breast Uni-ZAP XR LP03 HCAS CemCells, cyclohexamide Uni-ZAP XR LP03 treated, subtra HHPS HumanHippocampus, pBS LP03 subtracted HKCS HKCU Human Colon Cancer, pBS LP03subtracted HRGS Raji cells, cyclohexamide pBS LP03 treated, subtractedHSUT Supt cells, cyclohexamide pBS LP03 treated, differentiallyexpressed HT4S Activated T-Cells, 12 hrs, Uni-ZAP XR LP03 subtractedHCDA HCDB HCDC HCDD Human Chondrosarcoma Uni-ZAP XR LP03 HCDE HOAA HOABHOAC Human Osteosarcoma Uni-ZAP XR LP03 HTLA HTLB HTLC HTLD Human adulttestis, large Uni-ZAP XR LP03 HTLE HTLF inserts HLMA HLMC HLMD BreastLymph node cDNA Uni-ZAP XR LP03 library H6EA H6EB H6EC HL-60, PMA 4 HUni-ZAP XR LP03 HTXA HTXB HTXC HTXD Activated T-Cell Uni-ZAP XR LP03HTXE HTXF HTXG HTXH (12 hs)/Thiouridine labelledEco HNFA HNFB HNFC HNFDHuman Neutrophil, Activated Uni-ZAP XR LP03 HNFE HNFF HNFG HNFH HNFJHTOB HTOC HUMAN TONSILS, Uni-ZAP XR LP03 FRACTION 2 HMGB Human OB MG63control Uni-ZAP XR LP03 fraction I HOPB Human OB HOS control Uni-ZAP XRLP03 fraction I HORB Human OB HOS treated (10 nM Uni-ZAP XR LP03 E2)fraction I HSVA HSVB HSVC Human Chronic Synovitis Uni-ZAP XR LP03 HROAHUMAN STOMACH Uni-ZAP XR LP03 HBJA HBJB HBJC HBJD HUMAN B CELL Uni-ZAPXR LP03 HBJE HBJF HBJG HBJH LYMPHOMA HBJI HBJJ HBJK HCRA HCRB HCRC humancorpus colosum Uni-ZAP XR LP03 HODA HODB HODC HODD human ovarian cancerUni-ZAP XR LP03 HDSA Dermatofibrosarcoma Uni-ZAP XR LP03 ProtuberanceHMWA HMWB HMWC Bone Marrow Cell Line Uni-ZAP XR LP03 HMWD HMWE HMWF(RS4; 11) HMWG HMWH HMWI HMWJ HSOA stomach cancer (human) Uni-ZAP XRLP03 HERA SKIN Uni-ZAP XR LP03 HMDA Brain-medulloblastoma Uni-ZAP XRLP03 HGLA HGLB HGLD Glioblastoma Uni-ZAP XR LP03 HEAA H. AtrophicEndometrium Uni-ZAP XR LP03 HBCA HBCB H. Lymph node breast CancerUni-ZAP XR LP03 HPWT Human Prostate BPH, re- Uni-ZAP XR LP03 excisionHFVG HFVH HFVI Fetal Liver, subtraction II pBS LP03 HNFI HumanNeutrophils, pBS LP03 Activated, re-excision HBMB HBMC HBMD Human BoneMarrow, re- pBS LP03 excision HKML HKMM HKMN H. Kidney Medulla, re- pBSLP03 excision HKIX HKIY H. Kidney Cortex, subtracted pBS LP03 HADT H.Amygdala Depression, pBS LP03 subtracted H6AS Hl-60, untreated,subtracted Uni-ZAP XR LP03 H6ES HL-60, PMA 4 H, subtracted Uni-ZAP XRLP03 H6BS HL-60, RA 4 h, Subtracted Uni-ZAP XR LP03 H6CS HL-60, PMA 1 d,subtracted Uni-ZAP XR LP03 HTXJ HTXK Activated T- Uni-ZAP XR LP03cell(12 h)/Thiouridine-re- excision HMSA HMSB HMSC HMSD Monocyteactivated Uni-ZAP XR LP03 HMSE HMSF HMSG HMSH HMSI HMSJ HMSK HAGA HAGBHAGC HAGD Human Amygdala Uni-ZAP XR LP03 HAGE HAGF HSRA HSRB HSRESTROMAL - Uni-ZAP XR LP03 OSTEOCLASTOMA HSRD HSRF HSRG HSRH HumanOsteoclastoma Uni-ZAP XR LP03 Stromal Cells - unamplified HSQA HSQB HSQCHSQD Stromal cell TF274 Uni-ZAP XR LP03 HSQE HSQF HSQG HSKA HSKB HSKCHSKD Smooth muscle, serum treated Uni-ZAP XR LP03 HSKE HSKF HSKZ HSLAHSLB HSLC HSLD Smooth muscle, control Uni-ZAP XR LP03 HSLE HSLF HSLGHSDA HSDD HSDE HSDF Spinal cord Uni-ZAP XR LP03 HSDG HSDH HPWSProstate-BPH subtracted II pBS LP03 HSKW HSKX HSKY Smooth Muscle- HASTEpBS LP03 normalized HFPB HFPC HFPD H. Frontal cortex, epileptic; re-Uni-ZAP XR LP03 excision HSDI HSDJ HSDK Spinal Cord, re-excision Uni-ZAPXR LP03 HSKN HSKO Smooth Muscle Serum pBS LP03 Treated, Norm HSKG HSKHHSKI Smooth muscle, serum pBS LP03 induced, re-exc HFCA HFCB HFCC HFCDHuman Fetal Brain Uni-ZAP XR LP04 HFCE HFCF HPTA HPTB HPTD HumanPituitary Uni-ZAP XR LP04 HTHB HTHC HTHD Human Thymus Uni-ZAP XR LP04HE6B HE6C HE6D HE6E Human Whole Six Week Old Uni-ZAP XR LP04 HE6F HE6GHE6S Embryo HSSA HSSB HSSC HSSD Human Synovial Sarcoma Uni-ZAP XR LP04HSSE HSSF HSSG HSSH HSSI HSSJ HSSK HE7T 7 Week Old Early Stage Uni-ZAPXR LP04 Human, subtracted HEPA HEPB HEPC Human Epididymus Uni-ZAP XRLP04 HSNA HSNB HSNC HSNM Human Synovium Uni-ZAP XR LP04 HSNN HPFB HPFCHPFD HPFE Human Prostate Cancer, Uni-ZAP XR LP04 Stage C fraction HE2AHE2D HE2E HE2H 12 Week Old Early Stage Uni-ZAP XR LP04 HE2I HE2M HE2NHE2O Human HE2B HE2C HE2F HE2G 12 Week Old Early Stage Uni-ZAP XR LP04HE2P HE2Q Human, II HPTS HPTT HPTU Human Pituitary, subtracted Uni-ZAPXR LP04 HAUA HAUB HAUC Amniotic Cells - TNF Uni-ZAP XR LP04 induced HAQAHAQB HAQC HAQD Amniotic Cells - Primary Uni-ZAP XR LP04 Culture HWTAHWTB HWTC wilm's tumor Uni-ZAP XR LP04 HBSD Bone Cancer, re-excisionUni-ZAP XR LP04 HSGB Salivary gland, re-excision Uni-ZAP XR LP04 HSJAHSJB HSJC Smooth muscle-ILb induced Uni-ZAP XR LP04 HSXA HSXB HSXC HSXDHuman Substantia Nigra Uni-ZAP XR LP04 HSHA HSHB HSHC Smooth muscle,IL1b induced Uni-ZAP XR LP04 HOUA HOUB HOUC HOUD Adipocytes Uni-ZAP XRLP04 HOUE HPWA HPWB HPWC Prostate BPH Uni-ZAP XR LP04 HPWD HPWE HELAHELB HELC HELD Endothelial cells-control Uni-ZAP XR LP04 HELE HELF HELGHELH HEMA HEMB HEMC Endothelial-induced Uni-ZAP XR LP04 HEMD HEME HEMFHEMG HEMH HBIA HBIB HBIC Human Brain, Striatum Uni-ZAP XR LP04 HHSA HHSBHHSC HHSD Human Uni-ZAP XR LP04 HHSE Hypothalmus, Schizophrenia HNGAHNGB HNGC HNGD neutrophils control Uni-ZAP XR LP04 HNGE HNGF HNGG HNGHHNGI HNGJ HNHA HNHB HNHC HNHD Neutrophils IL-1 and LPS Uni-ZAP XR LP04HNHE HNHF HNHG HNHH induced HNHI HNHJ HSDB HSDC STRIATUM DEPRESSIONUni-ZAP XR LP04 HHPT Hypothalamus Uni-ZAP XR LP04 HSAT HSAU HSAV HSAWAnergic T-cell Uni-ZAP XR LP04 HSAX HSAY HSAZ HBMS HBMT HBMU Bone marrowUni-ZAP XR LP04 HBMV HBMW HBMX HOEA HOEB HOEC HOED Osteoblasts Uni-ZAPXR LP04 HOEE HOEF HOEJ HAIA HAIB HAIC HAID Epithelial-TNFa and INFUni-ZAP XR LP04 HAIE HAIF induced HTGA HTGB HTGC HTGD Apoptotic T-cellUni-ZAP XR LP04 HMCA HMCB HMCC Macrophage-oxLDL Uni-ZAP XR LP04 HMCDHMCE HMAA HMAB HMAC Macrophage (GM-CSF Uni-ZAP XR LP04 HMAD HMAE HMAFtreated) HMAG HPHA Normal Prostate Uni-ZAP XR LP04 HPIA HPIB HPIC LNCAPprostate cell line Uni-ZAP XR LP04 HPJA HPJB HPJC PC3 Prostate cell lineUni-ZAP XR LP04 HOSE HOSF HOSG Human Osteoclastoma, re- Uni-ZAP XR LP04excision HTGE HTGF Apoptotic T-cell, re-excision Uni-ZAP XR LP04 HMAJHMAK H Macrophage (GM-CSF Uni-ZAP XR LP04 treated), re-excision HACBHACC HACD Human Adipose Tissue, re- Uni-ZAP XR LP04 excision HFPA H.Frontal Cortex, Epileptic Uni-ZAP XR LP04 HFAA HFAB HFAC HFADAlzheimer's, spongy change Uni-ZAP XR LP04 HFAE HFAM Frontal Lobe,Dementia Uni-ZAP XR LP04 HMIA HMIB HMIC Human Manic Depression Uni-ZAPXR LP04 Tissue HTSA HTSE HTSF HTSG Human Thymus pBS LP05 HTSH HPBA HPBBHPBC HPBD Human Pineal Gland pBS LP05 HPBE HSAA HSAB HSAC HSA 172 CellspBS LP05 HSBA HSBB HSBC HSBM HSC172 cells pBS LP05 HJAA HJAB HJAC HJADJurkat T-cell G1 phase pBS LP05 HJBA HJBB HJBC HJBD Jurkat T-Cell, Sphase pBS LP05 HAFA HAFB Aorta endothelial cells + TNF-a pBS LP05 HAWAHAWB HAWC Human White Adipose pBS LP05 HTNA HTNB Human Thyroid pBS LP05HONA Normal Ovary, pBS LP05 Premenopausal HARA HARB Human Adult RetinapBS LP05 HLJA HLJB Human Lung pCMVSport 1 LP06 HOFM HOFN HOFO H. OvarianTumor, II, pCMVSport 2.0 LP07 OV5232 HOGA HOGB HOGC OV 10-3-95 pCMVSport2.0 LP07 HCGL CD34+cells, II pCMVSport 2.0 LP07 HDLA Hodgkin's LymphomaI pCMVSport 2.0 LP07 HDTA HDTB HDTC HDTD Hodgkin's Lymphoma II pCMVSport2.0 LP07 HDTE HKAA HKAB HKAC HKAD Keratinocyte pCMVSport 2.0 LP07 HKAEHKAF HKAG HKAH HCIM CAPFINDER, Crohn's pCMVSport 2.0 LP07 Disease, lib 2HKAL Keratinocyte, lib 2 pCMVSport 2.0 LP07 HKAT Keratinocyte, lib 3pCMVSport 2.0 LP07 HNDA Nasal polyps pCMVSport 2.0 LP07 HDRA H. PrimaryDendritic Cells, lib 3 pCMVSport 2.0 LP07 HOHA HOHB HOHC HumanOsteoblasts II pCMVSport 2.0 LP07 HLDA HLDB HLDC Liver, HepatomapCMVSport 3.0 LP08 HLDN HLDO HLDP Human Liver, normal pCMVSport 3.0 LP08HMTA pBMC stimulated w/ poly I/C pCMVSport 3.0 LP08 HNTA NTERA2, controlpCMVSport 3.0 LP08 HDPA HDPB HDPC HDPD Primary Dendritic Cells, lib 1pCMVSport 3.0 LP08 HDPF HDPG HDPH HDPI HDPJ HDPK HDPM HDPN HDPO HDPPPrimary Dendritic cells, frac 2 pCMVSport 3.0 LP08 HMUA HMUB HMUCMyoloid Progenitor Cell Line pCMVSport 3.0 LP08 HHEA HHEB HHEC HHED TCell helper I pCMVSport 3.0 LP08 HHEM HHEN HHEO HHEP T cell helper IIpCMVSport 3.0 LP08 HEQA HEQB HEQC Human endometrial stromal pCMVSport3.0 LP08 cells HJMA HJMB Human endometrial stromal pCMVSport 3.0 LP08cells-treated with progesterone HSWA HSWB HSWC Human endometrial stromalpCMVSport 3.0 LP08 cells-treated with estradiol HSYA HSYB HSYC HumanThymus Stromal Cells pCMVSport 3.0 LP08 HLWA HLWB HLWC Human PlacentapCMVSport 3.0 LP08 HRAA HRAB HRAC Rejected Kidney, lib 4 pCMVSport 3.0LP08 HMTM PCR, pBMC I/C treated PCRII LP09 HMJA H. Meniingima, M6 pSport1 LP10 HMKA HMKB HMKC H. Meningima, M1 pSport 1 LP10 HMKD HMKE HUSG HUSIHuman umbilical vein pSport 1 LP10 endothelial cells, IL-4 induced HUSXHUSY Human Umbilical Vein pSport 1 LP10 Endothelial Cells, uninducedHOFA Ovarian Tumor I, OV5232 pSport 1 LP10 HCFA HCFB HCFC HCFD T-CellPHA 16 hrs pSport 1 LP10 HCFL HCFM HCFN HCFO T-Cell PHA 24 hrs pSport 1LP10 HADA HADC HADD HADE Human Adipose pSport 1 LP10 HADF HADG HOVA HOVBHOVC Human Ovary pSport 1 LP10 HTWB HTWC HTWD Resting T-Cell Library, IIpSport 1 LP10 HTWE HTWF HMMA Spleen metastic melanoma pSport 1 LP10 HLYAHLYB HLYC HLYD Spleen, Chronic lymphocytic pSport 1 LP10 HLYE leukemiaHCGA CD34+ cell, I pSport 1 LP10 HEOM HEON Human Eosinophils pSport 1LP10 HTDA Human Tonsil, Lib 3 pSport 1 LP10 HSPA Salivary Gland, Lib 2pSport 1 LP10 HCHA HCHB HCHC Breast Cancer cell line, MDA pSport 1 LP1036 HCHM HCHN Breast Cancer Cell line, pSport 1 LP10 angiogenic HCIACrohn's Disease pSport 1 LP10 HDAA HDAB HDAC HEL cell line pSport 1 LP10HABA Human Astrocyte pSport 1 LP10 HUFA HUFB HUFC Ulcerative ColitispSport 1 LP10 HNTM NTERA2 + retinoic acid, 14 pSport 1 LP10 days HDQAPrimary Dendritic pSport 1 LP10 cells, CapFinder2, frac 1 HDQM PrimaryDendritic Cells, pSport 1 LP10 CapFinder, frac 2 HLDX Human Liver,pSport 1 LP10 normal, CapFinder HULA HULB HULC Human Dermal EndothelialpSport 1 LP10 Cells, untreated HUMA Human Dermal Endothelial pSport 1LP10 cells, treated HCJA Human Stromal Endometrial pSport 1 LP10fibroblasts, untreated HCJM Human Stromal endometrial pSport 1 LP10fibroblasts, treated w/ estradiol HEDA Human Stromal endometrial pSport1 LP10 fibroblasts, treated with progesterone HFNA Human ovary tumorcell pSport 1 LP10 OV350721 HKGA HKGB HKGC HKGD Merkel Cells pSport 1LP10 HISA HISB HISC Pancreas Islet Cell Tumor pSport 1 LP10 HLSA Skin,burned pSport 1 LP10 HBZA Prostate, BPH, Lib 2 pSport 1 LP10 HBZSProstate BPH, Lib 2, pSport 1 LP10 subtracted HFIA HFIB HFIC SynovialFibroblasts (control) pSport 1 LP10 HFIH HFII HFIJ Synovial hypoxiapSport 1 LP10 HFIT HFIU HFIV Synovial IL-1/TNF stimulated pSport 1 LP10HGCA Messangial cell, frac 1 pSport 1 LP10 HMVA HMVB HMVC Bone MarrowStromal Cell, pSport 1 LP10 untreated HFIX HFIY HFIZ SynovialFibroblasts pSport 1 LP10 (Il1/TNF), subt HFOX HFOY HFOZ Synovialhypoxia-RSF pSport 1 LP10 subtracted HMQA HMQB HMQC Human ActivatedMonocytes Uni-ZAP XR LP11 HMQD HLIA HLIB HLIC Human Liver pCMVSport 1LP012 HHBA HHBB HHBC HHBD Human Heart pCMVSport 1 LP012 HHBE HBBA HBBBHuman Brain pCMVSport 1 LP012 HLJA HLJB HLJC HLJD Human Lung pCMVSport 1LP012 HLJE HOGA HOGB HOGC Ovarian Tumor pCMVSport 2.0 LP012 HTJM HumanTonsils, Lib 2 pCMVSport 2.0 LP012 HAMF HAMG KMH2 pCMVSport 3.0 LP012HAJA HAJB HAJC L428 pCMVSport 3.0 LP012 HWBA HWBB HWBC Dendritic cells,pooled pCMVSport 3.0 LP012 HWBD HWBE HWAA HWAB HWAC Human Bone Marrow,pCMVSport 3.0 LP012 HWAD HWAE treated HYAA HYAB HYAC B Cell lymphomapCMVSport 3.0 LP012 HWHG HWHH HWHI Healing groin wound, 6.5 pCMVSport3.0 LP012 hours post incision HWHP HWHQ HWHR Healing groin wound; 7.5pCMVSport 3.0 LP012 hours post incision HARM Healing groin wound - zerohr pCMVSport 3.0 LP012 post-incision (control) HBIM Olfactoryepithelium; pCMVSport 3.0 LP012 nasalcavity HWDA Healing Abdomen wound;pCMVSport 3.0 LP012 70&90 min post incision HWEA Healing Abdomen Wound;15 pCMVSport 3.0 LP012 days post incision HWJA Healing Abdomen pCMVSport3.0 LP012 Wound; 21&29 days HNAL Human Tongue, frac 2 pSport 1 LP012HMJA H. Meniingima, M6 pSport 1 LP012 HMKA HMKB HMKC H. Meningima, M1pSport 1 LP012 HMKD HMKE HOFA Ovarian Tumor I, OV5232 pSport 1 LP012HCFA HCFB HCFC HCFD T-Cell PHA 16 hrs pSport 1 LP012 HCFL HCFM HCFN HCFOT-Cell PHA 24 hrs pSport 1 LP012 HMMA HMMB HMMC Spleen metastic melanomapSport 1 LP012 HTDA Human Tonsil, Lib 3 pSport 1 LP012 HDBA Human FetalThymus pSport 1 LP012 HDUA Pericardium pSport 1 LP012 HBZA Prostate,BPH, Lib 2 pSport 1 LP012 HWCA Larynx tumor pSport 1 LP012 HWKA Normallung pSport 1 LP012 HSMB Bone marrow stroma, treated pSport 1 LP012 HBHMNormal trachea pSport 1 LP012 HLFC Human Larynx pSport 1 LP012 HLRBSiebben Polyposis pSport 1 LP012 HNIA Mammary Gland pSport 1 LP012 HNJBPalate carcinoma pSport 1 LP012 HNKA Palate normal pSport 1 LP012 HMZAPharynx carcinoma pSport 1 LP012 HABG Cheek Carcinoma pSport 1 LP012HMZM Pharynx Carcinoma pSport 1 LP012 HDRM Larynx Carcinoma pSport 1LP012 HVAA Pancreas normal PCA4 No pSport 1 LP012 HICA Tongue carcinomapSport 1 LP012 HUKA HUKB HUKC HUKD Human Uterine Cancer Lambda ZAP IILP013 HUKE HFFA Human Fetal Brain, random Lambda ZAP II LP013 primedHTUA Activated T-cell labeled with Lambda ZAP II LP013 4-thioluri HBQAEarly Stage Human Brain, Lambda ZAP II LP013 random primed HMEB Humanmicrovascular Lambda ZAP II LP013 Endothelial cells, fract. B HUSH HumanUmbilical Vein Lambda ZAP II LP013 Endothelial cells, fract. A, re-excision HLQC HLQD Hepatocellular tumor, re- Lambda ZAP II LP013excision HTWJ HTWK HTWL Resting T-cell, re-excision Lambda ZAP II LP013HF6S Human Whole 6 week Old pBluescript LP013 Embryo (II), subt HHPSHuman Hippocampus, pBluescript LP013 subtracted HL1S LNCAP, differentialpBluescript LP013 expression HLHS HLHT Early Stage Human Lung,pBluescript LP013 Subtracted HSUS Supt cells, cyclohexamide pBluescriptLP013 treated, subtracted HSUT Supt cells, cyclohexamide pBluescriptLP013 treated, differentially expressed HSDS H. Striatum Depression,pBluescript LP013 subtracted HPTZ Human Pituitary, SubtractedpBluescript LP013 VII HSDX H. Striatum Depression, subt pBluescriptLP013 II HSDZ H. Striatum Depression, subt pBluescript LP013 HPBA HPBBHPBC HPBD Human Pineal Gland pBluescript SK− LP013 HPBE HRTA ColorectalTumor pBluescript SK− LP013 HSBA HSBB HSBC HSBM HSC172 cells pBluescriptSK− LP013 HJAA HJAB HJAC HJAD Jurkat T-cell G1 phase pBluescript SK−LP013 HJBA HJBB HJBC HJBD Jurkat T-cell, S1 phase pBluescript SK− LP013HTNA HTNB Human Thyroid pBluescript SK− LP013 HAHA HAHB Human AdultHeart Uni-ZAP XR LP013 HE6A Whole 6 week Old Embryo Uni-ZAP XR LP013HFCA HFCB HFCC HFCD Human Fetal Brain Uni-ZAP XR LP013 HFCE HFKC HFKDHFKE HFKF Human Fetal Kidney Uni-ZAP XR LP013 HFKG HGBA HGBD HGBE HGBFHuman Gall Bladder Uni-ZAP XR LP013 HGBG HPRA HPRB HPRC HPRD HumanProstate Uni-ZAP XR LP013 HTEA HTEB HTEC HTED Human Testes Uni-ZAP XRLP013 HTEE HTTA HTTB HTTC HTTD Human Testes Tumor Uni-ZAP XR LP013 HTTEHYBA HYBB Human Fetal Bone Uni-ZAP XR LP013 HFLA Human Fetal LiverUni-ZAP XR LP013 HHFB HHFC HHFD HHFE Human Fetal Heart Uni-ZAP XR LP013HHFF HUVB HUVC HUVD HUVE Human Umbilical Vein, End. Uni-ZAP XR LP013remake HTHB HTHC HTHD Human Thymus Uni-ZAP XR LP013 HSTA HSTB HSTC HSTDHuman Skin Tumor Uni-ZAP XR LP013 HTAA HTAB HTAC HTAD Human ActivatedT-cells Uni-ZAP XR LP013 HTAE HFEA HFEB HFEC Human Fetal EpitheliumUni-ZAP XR LP013 (skin) HJPA HJPB HJPC HJPD Human Jurkat MembraneUni-ZAP XR LP013 Bound Polysomes HESA Human Epithelioid Sarcoma Uni-ZAPXR LP013 HALS Human Adult Liver, Uni-ZAP XR LP013 Subtracted HFTA HFTBHFTC HFTD Human Fetal Dura Mater Uni-ZAP XR LP013 HCAA HCAB HCAC Cemcells, cyclohexamide Uni-ZAP XR LP013 treated HRGA HRGB HRGC HRGD RajiCells, cyclohexamide Uni-ZAP XR LP013 treated HE9A HE9B HE9C HE9D NineWeek Old Early Stage Uni-ZAP XR LP013 HE9E Human HSFA Human FibrosarcomaUni-ZAP XR LP013 HATA HATB HATC HATD Human Adrenal Gland Tumor Uni-ZAPXR LP013 HATE HTRA Human Trachea Tumor Uni-ZAP XR LP013 HE2A HE2D HE2EHE2H 12 Week Old Early Stage Uni-ZAP XR LP013 HE2I Human HE2B HE2C HE2FHE2G 12 Week Old Early Stage Uni-ZAP XR LP013 HE2P Human, II HNEA HNEBHNEC HNED Human Neutrophil Uni-ZAP XR LP013 HNEE HBGA Human PrimaryBreast Uni-ZAP XR LP013 Cancer HPTS HPTT HPTU Human Pituitary,subtracted Uni-ZAP XR LP013 HMQA HMQB HMQC Human Activated MonocytesUni-ZAP XR LP013 HMQD HOAA HOAB HOAC Human Osteosarcoma Uni-ZAP XR LP013HTOA HTOD HTOE HTOF human tonsils Uni-ZAP XR LP013 HTOG HMGB Human OBMG63 control Uni-ZAP XR LP013 fraction I HOPB Human OB HOS controlUni-ZAP XR LP013 fraction I HOQB Human OB HOS treated (1 nM Uni-ZAP XRLP013 E2) fraction I HAUA HAUB HAUC Amniotic Cells - TNF Uni-ZAP XRLP013 induced HAQA HAQB HAQC HAQD Amniotic Cells - Primary Uni-ZAP XRLP013 Culture HROA HROC HUMAN STOMACH Uni-ZAP XR LP013 HBJA HBJB HBJCHBJD HUMAN B CELL Uni-ZAP XR LP013 HBJE LYMPHOMA HODA HODB HODC HODDhuman ovarian cancer Uni-ZAP XR LP013 HCPA Corpus Callosum Uni-ZAP XRLP013 HSOA stomach cancer (human) Uni-ZAP XR LP013 HERA SKIN Uni-ZAP XRLP013 HMDA Brain-medulloblastoma Uni-ZAP XR LP013 HGLA HGLB HGLDGlioblastoma Uni-ZAP XR LP013 HWTA HWTB HWTC wilm's tumor Uni-ZAP XRLP013 HEAA H. Atrophic Endometrium Uni-ZAP XR LP013 HAPN HAPO HAPP HAPQHuman Adult Pulmonary; re- Uni-ZAP XR LP013 HAPR excision HLTG HLTHHuman T-cell lymphoma; re- Uni-ZAP XR LP013 excision HAHC HAHD HAHEHuman Adult Heart; re- Uni-ZAP XR LP013 excision HAGA HAGB HAGC HAGDHuman Amygdala Uni-ZAP XR LP013 HAGE HSJA HSJB HSJC Smooth muscle-ILbinduced Uni-ZAP XR LP013 HSHA HSHB HSHC Smooth muscle, IL1b inducedUni-ZAP XR LP013 HPWA HPWB HPWC Prostate BPH Uni-ZAP XR LP013 HPWD HPWEHPIA HPIB HPIC LNCAP prostate cell line Uni-ZAP XR LP013 HPJA HPJB HPJCPC3 Prostate cell line Uni-ZAP XR LP013 HBTA Bone Marrow Stroma, Uni-ZAPXR LP013 TNF&LPS ind HMCF HMCG HMCH HMCI Macrophage-oxLDL; re- Uni-ZAPXR LP013 HMCJ excision HAGG HAGH HAGI Human Amygdala; re-excisionUni-ZAP XR LP013 HACA H. Adipose Tissue Uni-ZAP XR LP013 HKFB K562 + PMA(36 hrs), re- ZAP Express LP013 excision HCWT HCWU HCWV CD34 positivecells (cord ZAP Express LP013 blood), re-ex HBWA Whole brain ZAP ExpressLP013 HBXA HBXB HBXC HBXD Human Whole Brain #2 - ZAP Express LP013 OligodT >1.5 Kb HAVM Temporal cortex-Alzheizmer pT-Adv LP014 HAVTHippocampus, Alzheimer pT-Adv LP014 Subtracted HHAS CHME Cell LineUni-ZAP XR LP014 HAJR Larynx normal pSport 1 LP014 HWLE HWLF HWLG ColonNormal pSport 1 LP014 HWLH HCRM HCRN HCRO Colon Carcinoma pSport 1 LP014HWLI HWLJ HWLK Colon Normal pSport 1 LP014 HWLQ HWLR HWLS Colon TumorpSport 1 LP014 HWLT HBFM Gastrocnemius Muscle pSport 1 LP014 HBOD HBOEQuadriceps Muscle pSport 1 LP014 HBKD HBKE Soleus Muscle pSport 1 LP014HCCM Pancreatic Langerhans pSport 1 LP014 HWGA Larynx carcinoma pSport 1LP014 HWGM HWGN Larynx carcinoma pSport 1 LP014 HWLA HWLB HWLC Normalcolon pSport 1 LP014 HWLM HWLN Colon Tumor pSport 1 LP014 HVAM HVAN HVAOPancreas Tumor pSport 1 LP014 HWGQ Larynx carcinoma pSport 1 LP014 HAQMHAQN Salivary Gland pSport 1 LP014 HASM Stomach; normal pSport 1 LP014HBCM Uterus; normal pSport 1 LP014 HCDM Testis; normal pSport 1 LP014HDJM Brain; normal pSport 1 LP014 HEFM Adrenal Gland, normal pSport 1LP014 HBAA Rectum normal pSport 1 LP014 HFDM Rectum tumour pSport 1LP014 HGAM Colon, normal pSport 1 LP014 HHMM Colon, tumour pSport 1LP014 HCLB HCLC Human Lung Cancer Lambda Zap II LP015 HRLA L1 Cell lineZAP Express LP015 HHAM Hypothalamus, Alzheimer's pCMVSport 3.0 LP015HKBA Ku 812F Basophils Line pSport 1 LP015 HS2S Saos2, DexamethosomepSport 1 LP016 Treated HA5A Lung Carcinoma A549 pSport 1 LP016 TNFalphaactivated HTFM TF-1 Cell Line GM-CSF pSport 1 LP016 Treated HYAS ThyroidTumour pSport 1 LP016 HUTS Larynx Normal pSport 1 LP016 HXOA LarynxTumor pSport 1 LP016 HEAH Ea.hy.926 cell line pSport 1 LP016 HINAAdenocarcinoma Human pSport 1 LP016 HRMA Lung Mesothelium pSport 1 LP016HLCL Human Pre-Differentiated Uni-Zap XR LP017 Adipocytes HS2A Saos2Cells pSport 1 LP020 HS2I Saos2 Cells; Vitamin D3 pSport 1 LP020 TreatedHUCM CHME Cell Line, untreated pSport 1 LP020 HEPN Aryepiglottis NormalpSport 1 LP020 HPSN Sinus Piniformis Tumour pSport 1 LP020 HNSA StomachNormal pSport 1 LP020 HNSM Stomach Tumour pSport 1 LP020 HNLA LiverNormal Met5No pSport 1 LP020 HUTA Liver Tumour Met 5 Tu pSport 1 LP020HOCN Colon Normal pSport 1 LP020 HOCT Colon Tumor pSport 1 LP020 HTNTTongue Tumour pSport 1 LP020 HLXN Larynx Normal pSport 1 LP020 HLXTLarynx Tumour pSport 1 LP020 HTYN Thymus pSport 1 LP020 HPLN PlacentapSport 1 LP020 HTNG Tongue Normal pSport 1 LP020 HZAA Thyroid Normal(SDCA2 No) pSport 1 LP020 HWES Thyroid Thyroiditis pSport 1 LP020 HFHDFicolled Human Stromal pTrip1Ex2 LP021 Cells, 5Fu treated HFHM, HFHNFicolled Human Stromal pTrip1Ex2 LP021 Cells, Untreated HPCI Hep G2Cells, lambda library lambda Zap-CMV LP021 XR HBCA, HBCB, HBCC H. Lymphnode breast Cancer Uni-ZAP XR LP021 HCOK Chondrocytes pSPORT1 LP022HDCA, HDCB, HDCC Dendritic Cells From CD34 pSPORT1 LP022 Cells HDMA,HDMB CD40 activated monocyte pSPORT1 LP022 dendritic cells HDDM, HDDN,HDDO LPS activated derived pSPORT1 LP022 dendritic cells HPCR Hep G2Cells, PCR library lambda Zap-CMV LP022 XR HAAA, HAAB, HAAC Lung, Cancer(4005313A3): pSPORT1 LP022 Invasive Poorly Differentiated LungAdenocarcinoma HIPA, HIPB, HIPC Lung, Cancer (4005163 B7): pSPORT1 LP022Invasive, Poorly Diff. Adenocarcinoma, Metastatic HOOH, HOOI Ovary,Cancer: (4004562 B6) pSPORT1 LP022 Papillary Serous Cystic Neoplasm, LowMalignant Pot HIDA Lung, Normal: (4005313 B1) pSPORT1 LP022 HUJA, HUJB,HUJC, HUJD, HUJE B-Cells pCMVSport 3.0 LP022 HNOA, HNOB, HNOC, HNODOvary, Normal: (9805C040R) pSPORT1 LP022 HNLM Lung, Normal: (4005313 B1)pSPORT1 LP022 HSCL Stromal Cells pSPORT1 LP022 HAAX Lung, Cancer:(4005313 A3) pSPORT1 LP022 Invasive Poorly-differentiated Metastaticlung adenocarcinoma HUUA, HUUB, HUUC, HUUD B-cells (unstimulated)pTrip1Ex2 LP022 HWWA, HWWB, HWWC, HWWD, B-cells (stimulated) pSPORT1LP022 HWWE, HWWF, HWWG HCCC Colon, Cancer: (9808C064R) pCMVSport 3.0LP023 HPDO HPDP HPDQ HPDR Ovary, Cancer (9809C332): pSport 1 LP023 HPDPoorly differentiated adenocarcinoma HPCO HPCP HPCQ HPCT Ovary, Cancer(15395A1F): pSport 1 LP023 Grade II Papillary Carcinoma HOCM HOCO HOCPHOCQ Ovary, Cancer: (15799A1F) pSport 1 LP023 Poorly differentiatedcarcinoma HCBM HCBN HCBO Breast, Cancer: (4004943 A5) pSport 1 LP023HNBT HNBU HNBV Breast, Normal: (4005522B2) pSport 1 LP023 HBCP HBCQBreast, Cancer: (4005522 A2) pSport 1 LP023 HBCJ Breast, Cancer:(9806C012R) pSport 1 LP023 HSAM HSAN Stromal cells 3.88 pSport 1 LP023HVCA HVCB HVCC HVCD Ovary, Cancer: (4004332 A2) pSport 1 LP023 HSCK HSENHSEO Stromal cells (HBM3.18) pSport 1 LP023 HSCP HSCQ stromal cell clone2.5 pSport 1 LP023 HUXA Breast Cancer: (4005385 A2) pSport 1 LP023 HCOMHCON HCOO HCOP Ovary, Cancer (4004650 A3): pSport 1 LP023 HCOQWell-Differentiated Micropapillary Serous Carcinoma HBNM Breast, Cancer:(9802C020E) pSport 1 LP023 HVVA HVVB HVVC HVVD Human Bone Marrow,treated pSport 1 LP023 HVVE

Two nonlimiting examples are provided below for isolating a particularclone from the deposited sample of plasmid cDNAs cited for that clone inTable 7. First, a plasmid is directly isolated by screening the clonesusing a polynucleotide probe corresponding to the nucleotide sequence ofSEQ ID NO:X.

Particularly, a specific polynucleotide with 30-40 nucleotides issynthesized using an Applied Biosystems DNA synthesizer according to thesequence reported. The oligonucleotide is labeled, for instance, with³²P-γ-ATP using T4 polynucleotide kinase and purified according toroutine methods. (E.g., Maniatis et al., Molecular Cloning: A LaboratoryManual, Cold Spring Harbor Press, Cold Spring, N.Y. (1982)). The plasmidmixture is transformed into a suitable host, as indicated above (such asXL-1 Blue (Stratagene)) using techniques known to those of skill in theart, such as those provided by the vector supplier or in relatedpublications or patents cited above. The transformants are plated on1.5% agar plates (containing the appropriate selection agent, e.g.,ampicillin) to a density of about 150 transformants (colonies) perplate. These plates are screened using Nylon membranes according toroutine methods for bacterial colony screening (e.g., Sambrook et al.,Molecular Cloning: A Laboratory Manual, 2nd Edit., (1989), Cold SpringHarbor Laboratory Press, pages 1.93 to 1.104), or other techniques knownto those of skill in the art.

Alternatively, two primers of 17-20 nucleotides derived from both endsof the nucleotide sequence of SEQ ID NO:X are synthesized and used toamplify the desired cDNA using the deposited cDNA plasmid as a template.The polymerase chain reaction is carried out under routine conditions,for instance, in 25 μl of reaction mixture with 0.5 ug of the above cDNAtemplate. A convenient reaction mixture is 1.5-5 mM MgCl₂, 0.01% (w/v)gelatin, 20 μM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primerand 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturationat 94° C. for 1 min; annealing at 55° C. for 1 min; elongation at 72° C.for 1 min) are performed with a Perkin-Elmer Cetus automated thermalcycler. The amplified product is analyzed by agarose gel electrophoresisand the DNA band with expected molecular weight is excised and purified.The PCR product is verified to be the selected sequence by subcloningand sequencing the DNA product.

Several methods are available for the identification of the 5′ or 3′non-coding portions of a gene which may not be present in the depositedclone. These methods include but are not limited to, filter probing,clone enrichment using specific probes, and protocols similar oridentical to 5′ and 3′ “RACE” protocols which are well known in the art.For instance, a method similar to 5′ RACE is available for generatingthe missing 5′ end of a desired full-length transcript. (Fromont-Racineet al., Nucleic Acids Res. 21(7):1683-1684 (1993)).

Briefly, a specific RNA oligonucleotide is ligated to the 5′ ends of apopulation of RNA presumably containing full-length gene RNAtranscripts. A primer set containing a primer specific to the ligatedRNA oligonucleotide and a primer specific to a known sequence of thegene of interest is used to PCR amplify the 5′ portion of the desiredfull-length gene. This amplified product may then be sequenced and usedto generate the full length gene.

This above method starts with total RNA isolated from the desiredsource, although poly-A+ RNA can be used. The RNA preparation can thenbe treated with phosphatase if necessary to eliminate 5′ phosphategroups on degraded or damaged RNA which may interfere with the later RNAligase step. The phosphatase should then be inactivated and the RNAtreated with tobacco acid pyrophosphatase in order to remove the capstructure present at the 5′ ends of messenger RNAs. This reaction leavesa 5′ phosphate group at the 5′ end of the cap cleaved RNA which can thenbe ligated to an RNA oligonucleotide using T4 RNA ligase.

This modified RNA preparation is used as a template for first strandcDNA synthesis using a gene specific oligonucleotide. The first strandsynthesis reaction is used as a template for PCR amplification of thedesired 5′ end using a primer specific to the ligated RNAoligonucleotide and a primer specific to the known sequence of the geneof interest. The resultant product is then sequenced and analyzed toconfirm that the 5′ end sequence belongs to the desired gene.

Example 2 Isolation of Genomic Clones Corresponding to a Polynucleotide

A human genomic P1 library (Genomic Systems, Inc.) is screened by PCRusing primers selected for the sequence corresponding to SEQ ID NO:Xaccording to the method described in Example 1. (See also, Sambrook.)

Example 3 Tissue Specific Expression Analysis

The Human Genome Sciences, Inc. (HGS) database is derived fromsequencing tissue and/or disease specific cDNA libraries. Librariesgenerated from a particular tissue are selected and the specific tissueexpression pattern of EST groups or assembled contigs within theselibraries is determined by comparison of the expression patterns ofthose groups or contigs within the entire database. ESTs and assembledcontigs which show tissue specific expression are selected.

The original clone from which the specific EST sequence was generated,or in the case of an assembled contig, the clone from which the 5′ mostEST sequence was generated, is obtained from the catalogued library ofclones and the insert amplified by PCR using methods known in the art.The PCR product is denatured and then transferred in 96 or 384 wellformat to a nylon membrane (Schleicher and Scheull) generating an arrayfilter of tissue specific clones. Housekeeping genes, maize genes, andknown tissue specific genes are included on the filters. These targetscan be used in signal normalization and to validate assay sensitivity.Additional targets are included to monitor probe length and specificityof hybridization.

Radioactively labeled hybridization probes are generated by first strandcDNA synthesis per the manufacturer's instructions (Life Technologies)from mRNA/RNA samples prepared from the specific tissue being analyzed(e.g., prostate, prostate cancer, ovarian, ovarian cancer, etc.). Thehybridization probes are purified by gel exclusion chromatography,quantitated, and hybridized with the array filters in hybridizationbottles at 65° C. overnight. The filters are washed under stringentconditions and signals are captured using a Fuji phosphorimager.

Data is extracted using AIS software and following backgroundsubtraction, signal normalization is performed. This includes anormalization of filter-wide expression levels between differentexperimental runs. Genes that are differentially expressed in the tissueof interest are identified.

Example 4 Chromosomal Mapping of the Polynucleotides

An oligonucleotide primer set is designed according to the sequence atthe 5′ end of SEQ ID NO:X. This primer preferably spans about 100nucleotides. This primer set is then used in a polymerase chain reactionunder the following set of conditions: 30 seconds, 95° C.; 1 minute, 56°C.; 1 minute, 70° C. This cycle is repeated 32 times followed by one 5minute cycle at 70° C. Human, mouse, and hamster DNA is used as templatein addition to a somatic cell hybrid panel containing individualchromosomes or chromosome fragments (Bios, Inc). The reactions areanalyzed on either 8% polyacrylamide gels or 3.5% agarose gels.Chromosome mapping is determined by the presence of an approximately 100bp PCR fragment in the particular somatic cell hybrid.

Example 5 Bacterial Expression of a Polypeptide

A polynucleotide encoding a polypeptide of the present invention isamplified using PCR oligonucleotide primers corresponding to the 5′ and3′ ends of the DNA sequence, as outlined in Example 1, to synthesizeinsertion fragments. The primers used to amplify the cDNA insert shouldpreferably contain restriction sites, such as BamHI and XbaI, at the 5′end of the primers in order to clone the amplified product into theexpression vector. For example, BamHI and XbaI correspond to therestriction enzyme sites on the bacterial expression vector pQE-9.(Qiagen, Inc., Chatsworth, Calif.). This plasmid vector encodesantibiotic resistance (Amp^(r)), a bacterial origin of replication(ori), an IPTG-regulatable promoter/operator (P/O), a ribosome bindingsite (RBS), a 6-histidine tag (6-His), and restriction enzyme cloningsites.

The pQE-9 vector is digested with BamHI and XbaI and the amplifiedfragment is ligated into the pQE-9 vector maintaining the reading frameinitiated at the bacterial RBS. The ligation mixture is then used totransform the E. coli strain M15/rep4 (Qiagen, Inc.) which containsmultiple copies of the plasmid pREP4, which expresses the lacI repressorand also confers kanamycin resistance (Kan^(r)). Transformants areidentified by their ability to grow on LB plates andampicillin/kanamycin resistant colonies are selected. Plasmid DNA isisolated and confirmed by restriction analysis.

Clones containing the desired constructs are grown overnight (O/N) inliquid culture in LB media supplemented with both Amp (100 ug/ml) andKan (25 ug/ml). The O/N culture is used to inoculate a large culture ata ratio of 1:100 to 1:250. The cells are grown to an optical density 600(O.D.⁶⁰⁰) of between 0.4 and 0.6. IPTG (Isopropyl-B-D-thiogalactopyranoside) is then added to a final concentration of 1 mM. IPTG inducesby inactivating the lacI repressor, clearing the P/O leading toincreased gene expression.

Cells are grown for an extra 3 to 4 hours. Cells are then harvested bycentrifugation (20 mins at 6000×g). The cell pellet is solubilized inthe chaotropic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at4° C. The cell debris is removed by centrifugation, and the supernatantcontaining the polypeptide is loaded onto a nickel-nitrilo-tri-aceticacid (“Ni-NTA”) affinity resin column (available from QIAGEN, Inc.,supra). Proteins with a 6×His tag bind to the Ni-NTA resin with highaffinity and can be purified in a simple one-step procedure (for detailssee: The QIAexpressionist (1995) QIAGEN, Inc., supra).

Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCl,pH 8. The column is first washed with 10 volumes of 6 M guanidine-HCl,pH 8, then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finallythe polypeptide is eluted with 6 M guanidine-HCl, pH 5.

The purified protein is then renatured by dialyzing it againstphosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus200 mM NaCl. Alternatively, the protein can be successfully refoldedwhile immobilized on the Ni-NTA column. The recommended conditions areas follows: renature using a linear 6M-1M urea gradient in 500 mM NaCl,20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors. Therenaturation should be performed over a period of 1.5 hours or more.After renaturation the proteins are eluted by the addition of 250 mMimmidazole. Immidazole is removed by a final dialyzing step against PBSor 50 mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purifiedprotein is stored at 4° C. or frozen at −80° C.

In addition to the above expression vector, the present inventionfurther includes an expression vector, called pHE4a (ATCC AccessionNumber 209645, deposited on Feb. 25, 1998) which contains phage operatorand promoter elements operatively linked to a polynucleotide of thepresent invention, called pHE4a. (ATCC Accession Number 209645,deposited on Feb. 25, 1998.) This vector contains: 1) aneomycinphosphotransferase gene as a selection marker, 2) an E. coliorigin of replication, 3) a T5 phage promoter sequence, 4) two lacoperator sequences, 5) a Shine-Delgamo sequence, and 6) the lactoseoperon repressor gene (lacIq). The origin of replication (oriC) isderived from pUC19 (LTI, Gaithersburg, Md.). The promoter and operatorsequences are made synthetically.

DNA can be inserted into the pHE4a by restricting the vector with NdeIand XbaI, BamHI, XhoI, or Asp718, running the restricted product on agel, and isolating the larger fragment (the stuffer fragment should beabout 310 base pairs). The DNA insert is generated according to the PCRprotocol described in Example 1, using PCR primers having restrictionsites for NdeI (5′ primer) and XbaI, BamHI, XhoI, or Asp718 (3′ primer).The PCR insert is gel purified and restricted with compatible enzymes.The insert and vector are ligated according to standard protocols.

The engineered vector could easily be substituted in the above protocolto express protein in a bacterial system.

Example 6 Purification of a Polypeptide from an Inclusion Body

The following alternative method can be used to purify a polypeptideexpressed in E coli when it is present in the form of inclusion bodies.Unless otherwise specified, all of the following steps are conducted at4-10° C.

Upon completion of the production phase of the E. coli fermentation, thecell culture is cooled to 4-10° C. and the cells harvested by continuouscentrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of theexpected yield of protein per unit weight of cell paste and the amountof purified protein required, an appropriate amount of cell paste, byweight, is suspended in a buffer solution containing 100 mM Tris, 50 mMEDTA, pH 7.4. The cells are dispersed to a homogeneous suspension usinga high shear mixer.

The cells are then lysed by passing the solution through amicrofluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at4000-6000 psi. The homogenate is then mixed with NaCl solution to afinal concentration of 0.5 M NaCl, followed by centrifugation at 7000×gfor 15 min. The resultant pellet is washed again using 0.5M NaCl, 100 mMTris, 50 mM EDTA, pH 7.4.

The resulting washed inclusion bodies are solubilized with 1.5 Mguanidine hydrochloride (GuHCl) for 2-4 hours. After 7000×gcentrifugation for 15 min., the pellet is discarded and the polypeptidecontaining supernatant is incubated at 4° C. overnight to allow furtherGuHCl extraction.

Following high speed centrifugation (30,000×g) to remove insolubleparticles, the GuHCl solubilized protein is refolded by quickly mixingthe GuHCl extract with 20 volumes of buffer containing 50 mM sodium, pH4.5, 150 mM NaCl, 2 mM EDTA by vigorous stirring. The refolded dilutedprotein solution is kept at 4° C. without mixing for 12 hours prior tofurther purification steps.

To clarify the refolded polypeptide solution, a previously preparedtangential filtration unit equipped with 0.16 μm membrane filter withappropriate surface area (e.g., Filtron), equilibrated with 40 mM sodiumacetate, pH 6.0 is employed. The filtered sample is loaded onto a cationexchange resin (e.g., Poros HS-50, Perseptive Biosystems). The column iswashed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM,1000 mM, and 1500 mM NaCl in the same buffer, in a stepwise manner. Theabsorbance at 280 nm of the effluent is continuously monitored.Fractions are collected and further analyzed by SDS-PAGE.

Fractions containing the polypeptide are then pooled and mixed with 4volumes of water. The diluted sample is then loaded onto a previouslyprepared set of tandem columns of strong anion (Poros HQ-50, PerseptiveBiosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchangeresins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0.Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCl.The CM-20 column is then eluted using a 10 column volume linear gradientranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCl, 50mM sodium acetate, pH 6.5. Fractions are collected under constant A₂₈₀monitoring of the effluent. Fractions containing the polypeptide(determined, for instance, by 16% SDS-PAGE) are then pooled.

The resultant polypeptide should exhibit greater than 95% purity afterthe above refolding and purification steps. No major contaminant bandsshould be observed from Commassie blue stained 16% SDS-PAGE gel when 5μg of purified protein is loaded. The purified protein can also betested for endotoxin/LPS contamination, and typically the LPS content isless than 0.1 ng/ml according to LAL assays.

Example 7 Cloning and Expression of a Polypeptide in a BaculovirusExpression System

In this example, the plasmid shuttle vector pA2 is used to insert apolynucleotide into a baculovirus to express a polypeptide. Thisexpression vector contains the strong polyhedrin promoter of theAutographa californica nuclear polyhedrosis virus (AcMNPV) followed byconvenient restriction sites such as BamHI, Xba I and Asp718. Thepolyadenylation site of the simian virus 40 (“SV40”) is used forefficient polyadenylation. For easy selection of recombinant virus, theplasmid contains the beta-galactosidase gene from E. coli under controlof a weak Drosophila promoter in the same orientation, followed by thepolyadenylation signal of the polyhedrin gene. The inserted genes areflanked on both sides by viral sequences for cell-mediated homologousrecombination with wild-type viral DNA to generate a viable virus thatexpress the cloned polynucleotide.

Many other baculovirus vectors can be used in place of the vector above,such as pAc373, pVL941, and pAcIM1, as one skilled in the art wouldreadily appreciate, as long as the construct provides appropriatelylocated signals for transcription, translation, secretion and the like,including a signal peptide and an in-frame AUG as required. Such vectorsare described, for instance, in Luckow et al., Virology 170:31-39(1989).

Specifically, the cDNA sequence contained in the deposited clone,including the AUG initiation codon, is amplified using the PCR protocoldescribed in Example 1. If a naturally occurring signal sequence is usedto produce the polypeptide of the present invention, the pA2 vector doesnot need a second signal peptide. Alternatively, the vector can bemodified (pA2 GP) to include a baculovirus leader sequence, using thestandard methods described in Summers et al., “A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures,” TexasAgricultural Experimental Station Bulletin No. 1555 (1987).

The amplified fragment is isolated from a 1% agarose gel using acommercially available kit (“Geneclean,” BIO 101 Inc., La Jolla,Calif.). The fragment then is digested with appropriate restrictionenzymes and again purified on a 1% agarose gel.

The plasmid is digested with the corresponding restriction enzymes andoptionally, can be dephosphorylated using calf intestinal phosphatase,using routine procedures known in the art. The DNA is then isolated froma 1% agarose gel using a commercially available kit (“Geneclean” BIO 101Inc., La Jolla, Calif.).

The fragment and the dephosphorylated plasmid are ligated together withT4 DNA ligase. E. coli HB101 or other suitable E. coli hosts such asXL-1 Blue (Stratagene Cloning Systems, La Jolla, Calif.) cells aretransformed with the ligation mixture and spread on culture plates.Bacteria containing the plasmid are identified by digesting DNA fromindividual colonies and analyzing the digestion product by gelelectrophoresis. The sequence of the cloned fragment is confirmed by DNAsequencing.

Five μg of a plasmid containing the polynucleotide is co-transfectedwith 1.0 μg of a commercially available linearized baculovirus DNA(“BaculoGold™ baculovirus DNA, Pharmingen, San Diego, Calif.), using thelipofection method described by Felgner et al., Proc. Natl. Acad. Sci.USA 84:7413-7417 (1987). One μg of BaculoGold™ virus DNA and 5 μg of theplasmid are mixed in a sterile well of a microtiter plate containing 50μl of serum-free Grace's medium (Life Technologies Inc., Gaithersburg,Md.). Afterwards, 10 μl Lipofectin plus 90 μl Grace's medium are added,mixed and incubated for 15 minutes at room temperature. Then thetransfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL1711) seeded in a 35 mm tissue culture plate with 1 ml Grace's mediumwithout serum. The plate is then incubated for 5 hours at 27° C. Thetransfection solution is then removed from the plate and 1 ml of Grace'sinsect medium supplemented with 10% fetal calf serum is added.Cultivation is then continued at 27° C. for four days.

After four days the supernatant is collected and a plaque assay isperformed, as described by Summers and Smith, supra. An agarose gel with“Blue Gal” (Life Technologies Inc., Gaithersburg) is used to allow easyidentification and isolation of gal-expressing clones, which produceblue-stained plaques. (A detailed description of a “plaque assay” ofthis type can also be found in the user's guide for insect cell cultureand baculovirology distributed by Life Technologies Inc., Gaithersburg,page 9-10.) After appropriate incubation, blue stained plaques arepicked with the tip of a micropipettor (e.g., Eppendorf). The agarcontaining the recombinant viruses is then resuspended in amicrocentrifuge tube containing 200 μl of Grace's medium and thesuspension containing the recombinant baculovirus is used to infect Sf9cells seeded in 35 mm dishes. Four days later the supernatants of theseculture dishes are harvested and then they are stored at 4° C.

To verify the expression of the polypeptide, Sf9 cells are grown inGrace's medium supplemented with 10% heat-inactivated FBS. The cells areinfected with the recombinant baculovirus containing the polynucleotideat a multiplicity of infection (“MOI”) of about 2. If radiolabeledproteins are desired, 6 hours later the medium is removed and isreplaced with SF900 II medium minus methionine and cysteine (availablefrom Life Technologies Inc., Rockville, Md.). After 42 hours, 5 μCi of³⁵S-methionine and 5 μCi ³⁵S-cysteine (available from Amersham) areadded. The cells are further incubated for 16 hours and then areharvested by centrifugation. The proteins in the supernatant as well asthe intracellular proteins are analyzed by SDS-PAGE followed byautoradiography (if radiolabeled).

Microsequencing of the amino acid sequence of the amino terminus ofpurified protein may be used to determine the amino terminal sequence ofthe produced protein.

Example 8 Expression of a Polypeptide in Mammalian Cells

The polypeptide of the present invention can be expressed in a mammaliancell. A typical mammalian expression vector contains a promoter element,which mediates the initiation of transcription of mRNA, a protein codingsequence, and signals required for the termination of transcription andpolyadenylation of the transcript. Additional elements includeenhancers, Kozak sequences and intervening sequences flanked by donorand acceptor sites for RNA splicing. Highly efficient transcription isachieved with the early and late promoters from SV40, the long terminalrepeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the earlypromoter of the cytomegalovirus (CMV). However, cellular elements canalso be used (e.g., the human actin promoter).

Suitable expression vectors for use in practicing the present inventioninclude, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala,Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBC12MI (ATCC67109), pCMVSport 2.0, and pCMVSport 3.0. Mammalian host cells thatcould be used include, human Hela, 293, H9 and Jurkat cells, mouseNIH3T3 and C127 cells, Cos 1, Cos 7 and CVI, quail QC1-3 cells, mouse Lcells and Chinese hamster ovary (CHO) cells.

Alternatively, the polypeptide can be expressed in stable cell linescontaining the polynucleotide integrated into a chromosome. Theco-transfection with a selectable marker such as DHFR, gpt, neomycin, orhygromycin allows the identification and isolation of the transfectedcells.

The transfected gene can also be amplified to express large amounts ofthe encoded protein. The DHFR (dihydrofolate reductase) marker is usefulin developing cell lines that carry several hundred or even severalthousand copies of the gene of interest. (See, e.g., Alt, F. W., et al.,J. Biol. Chem. 253:1357-1370 (1978); Hamlin, J. L. and Ma, C., Biochem.et Biophys. Acta, 1097:107-143 (1990); Page, M. J. and Sydenham, M. A.,Biotechnology 9:64-68 (1991)). Another useful selection marker is theenzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279(1991); Bebbington et al., Bio/Technology 10:169-175 (1992). Using thesemarkers, the mammalian cells are grown in selective medium and the cellswith the highest resistance are selected. These cell lines contain theamplified gene(s) integrated into a chromosome. Chinese hamster ovary(CHO) and NSO cells are often used for the production of proteins.

Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), theexpression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCCAccession No. 209647) contain the strong promoter (LTR) of the RousSarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447(March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell41:521-530 (1985)). Multiple cloning sites, e.g., with the restrictionenzyme cleavage sites BamHI, XbaI and Asp718, facilitate the cloning ofthe gene of interest. The vectors also contain the 3′ intron, thepolyadenylation and termination signal of the rat preproinsulin gene,and the mouse DHFR gene under control of the SV40 early promoter.

Specifically, the plasmid pC6, for example, is digested with appropriaterestriction enzymes and then dephosphorylated using calf intestinalphosphates by procedures known in the art. The vector is then isolatedfrom a 1% agarose gel.

A polynucleotide of the present invention is amplified according to theprotocol outlined in Example 1. If a naturally occurring signal sequenceis used to produce the polypeptide of the present invention, the vectordoes not need a second signal peptide. Alternatively, if a naturallyoccurring signal sequence is not used, the vector can be modified toinclude a heterologous signal sequence. (See, e.g., InternationalPublication No. WO 96/34891.)

The amplified fragment is isolated from a 1% agarose gel using acommercially available kit (“Geneclean,” BIO 101 Inc., La Jolla,Calif.). The fragment then is digested with appropriate restrictionenzymes and again purified on a 1% agarose gel.

The amplified fragment is then digested with the same restriction enzymeand purified on a 1% agarose gel. The isolated fragment and thedephosphorylated vector are then ligated with T4 DNA ligase. E. coliHB101 or XL-1 Blue cells are then transformed and bacteria areidentified that contain the fragment inserted into plasmid pC6 using,for instance, restriction enzyme analysis.

Chinese hamster ovary cells lacking an active DHFR gene is used fortransfection. Five μg of the expression plasmid pC6 or pC4 iscotransfected with 0.5 μg of the plasmid pSVneo using lipofectin(Felgner et al., supra). The plasmid pSV2-neo contains a dominantselectable marker, the neo gene from Tn5 encoding an enzyme that confersresistance to a group of antibiotics including G418. The cells areseeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days,the cells are trypsinized and seeded in hybridoma cloning plates(Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50ng/ml of methotrexate plus 1 mg/ml G418. After about 10-14 days singleclones are trypsinized and then seeded in 6-well petri dishes or 10 mlflasks using different concentrations of methotrexate (50 n™, 100 nM,200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations ofmethotrexate are then transferred to new 6-well plates containing evenhigher concentrations of methotrexate (1 μM, 2 μM, 5 μM, 10 mM, 20 mM).The same procedure is repeated until clones are obtained which grow at aconcentration of 100-200 μM. Expression of the desired gene product isanalyzed, for instance, by SDS-PAGE and Western blot or by reversedphase HPLC analysis.

Example 9 Protein Fusions

The polypeptides of the present invention are preferably fused to otherproteins. These fusion proteins can be used for a variety ofapplications. For example, fusion of the present polypeptides toHis-tag, HA-tag, protein A, IgG domains, and maltose binding proteinfacilitates purification. (See Example 5; see also EP A 394,827;Traunecker, et al., Nature 331:84-86 (1988)). Similarly, fusion toIgG-1, IgG-3, and albumin increases the halflife time in vivo. Nuclearlocalization signals fused to the polypeptides of the present inventioncan target the protein to a specific subcellular localization, whilecovalent heterodimer or homodimers can increase or decrease the activityof a fusion protein. Fusion proteins can also create chimeric moleculeshaving more than one function. Finally, fusion proteins can increasesolubility and/or stability of the fused protein compared to thenon-fused protein. All of the types of fusion proteins described abovecan be made by modifying the following protocol, which outlines thefusion of a polypeptide to an IgG molecule, or the protocol described inExample 5.

Briefly, the human Fc portion of the IgG molecule can be PCR amplified,using primers that span the 5′ and 3′ ends of the sequence describedbelow. These primers also should have convenient restriction enzymesites that will facilitate cloning into an expression vector, preferablya mammalian expression vector.

For example, if pC4 (ATCC Accession No. 209646) is used, the human Fcportion can be ligated into the BamHI cloning site. Note that the 3′BamHI site should be destroyed. Next, the vector containing the human Fcportion is re-restricted with BamHI, linearizing the vector, and apolynucleotide of the present invention, isolated by the PCR protocoldescribed in Example 1, is ligated into this BamHI site. Note that thepolynucleotide is cloned without a stop codon, otherwise a fusionprotein will not be produced.

If the naturally occurring signal sequence is used to produce thepolypeptide of the present invention, pC4 does not need a second signalpeptide. Alternatively, if the naturally occurring signal sequence isnot used, the vector can be modified to include a heterologous signalsequence. (See, e.g., International Publication No. WO 96/34891.) HumanIgG Fc region: GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACAC (SEQ ID NO:1)ATGCCCACCGTGCCCAGCACCTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGTGGTGGTGGACGTAAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAACCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA ATGAGTGCGACGGCCGCGACTCTAGAGGAT

Example 10 Production of an Antibody from a Polypeptide

a) Hybridoma Technology

The antibodies of the present invention can be prepared by a variety ofmethods. (See, Current Protocols, Chapter 2.) As one example of suchmethods, cells expressing a polypeptide of the present invention areadministered to an animal to induce the production of sera containingpolyclonal antibodies. In a preferred method, a preparation of apolypeptide of the present invention is prepared and purified to renderit substantially free of natural contaminants. Such a preparation isthen introduced into an animal in order to produce polyclonal antiseraof greater specific activity.

Monoclonal antibodies specific for a polypeptide of the presentinvention are prepared using hybridoma technology (Kohler et al., Nature256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler etal., Eur. J. Immunol. 6:292 (1976); Hammerling et al., in: MonoclonalAntibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)).In general, an animal (preferably a mouse) is immunized with apolypeptide of the present invention or, more preferably, with asecreted polypeptide-expressing cell. Such polypeptide-expressing cellsare cultured in any suitable tissue culture medium, preferably inEarle's modified Eagle's medium supplemented with 10% fetal bovine serum(inactivated at about 56° C.), and supplemented with about 10 g/l ofnonessential amino acids, about 1,000 U/ml of penicillin, and about 100μg/ml of streptomycin.

The splenocytes of such mice are extracted and fused with a suitablemyeloma cell line. Any suitable myeloma cell line may be employed inaccordance with the present invention; however, it is preferable toemploy the parent myeloma cell line (SP20), available from the ATCC.After fusion, the resulting hybridoma cells are selectively maintainedin HAT medium, and then cloned by limiting dilution as described byWands et al. (Gastroenterology 80:225-232 (1981)). The hybridoma cellsobtained through such a selection are then assayed to identify cloneswhich secrete antibodies capable of binding the polypeptide of thepresent invention.

Alternatively, additional antibodies capable of binding to a polypeptideof the present invention can be produced in a two-step procedure usinganti-idiotypic antibodies. Such a method makes use of the fact thatantibodies are themselves antigens, and therefore, it is possible toobtain an antibody which binds to a second antibody. In accordance withthis method, protein specific antibodies are used to immunize an animal,preferably a mouse. The splenocytes of such an animal are then used toproduce hybridoma cells, and the hybridoma cells are screened toidentify clones which produce an antibody whose ability to bind to thepolypeptide-specific antibody can be blocked by said polypeptide. Suchantibodies comprise anti-idiotypic antibodies to thepolypeptide-specific antibody and are used to immunize an animal toinduce formation of further polypeptide-specific antibodies.

For in vivo use of antibodies in humans, an antibody is “humanized”.Such antibodies can be produced using genetic constructs derived fromhybridoma cells producing the monoclonal antibodies described above.Methods for producing chimeric and humanized antibodies are known in theart and are discussed herein. (See, for review, Morrison, Science229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al.,U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al.,EP 173494; Neuberger et al., WO 8601533; Robinson et al., InternationalPublication No. WO 8702671; Boulianne et al., Nature 312:643 (1984);Neuberger et al., Nature 314:268 (1985)).

B) Isolation of Antibody Fragments Directed Against a Polypeptide of thePresent Invention from a Library of scFvs

Naturally occurring V-genes isolated from human PBLs are constructedinto a library of antibody fragments which contain reactivities againsta polypeptide of the present invention to which the donor may or may nothave been exposed (see e.g., U.S. Pat. No. 5,885,793 incorporated hereinby reference in its entirety).

Rescue of the Library. A library of scFvs is constructed from the RNA ofhuman PBLs as described in International Publication No. WO 92/01047. Torescue phage displaying antibody fragments, approximately 10⁹ E. coliharboring the phagemid are used to inoculate 50 ml of 2×TY containing 1%glucose and 100 μg/ml of ampicillin (2×TY-AMP-GLU) and grown to an O.D.of 0.8 with shaking. Five ml of this culture is used to inoculate 50 mlof 2×TY-AMP-GLU, 2×108 TU of delta gene 3 helper (M13 delta gene III,see International Publication No. WO 92/01047) are added and the cultureincubated at 37° C. for 45 minutes without shaking and then at 37° C.for 45 minutes with shaking. The culture is centrifuged at 4000 r.p.m.for 10 min. and the pellet resuspended in 2 liters of 2×TY containing100 μg/ml ampicillin and 50 ug/ml kanamycin and grown overnight. Phageare prepared as described in International Publication No. WO 92/01047.

M13 delta gene III is prepared as follows: M13 delta gene III helperphage does not encode gene III protein, hence the phage (mid) displayingantibody fragments have a greater avidity of binding to antigen.Infectious M13 delta gene III particles are made by growing the helperphage in cells harboring a pUC19 derivative supplying the wild type geneIII protein during phage morphogenesis. The culture is incubated for 1hour at 37° C. without shaking and then for a further hour at 37° C.with shaking. Cells are spun down (IEC-Centra 8,400 r.p.m. for 10 min),resuspended in 300 ml 2×TY broth containing 100 μg ampicillin/ml and 25μg kanarnycin/ml (2×TY-AMP-KAN) and grown overnight, shaking at 37° C.Phage particles are purified and concentrated from the culture medium bytwo PEG-precipitations (Sambrook et al., 1990), resuspended in 2 ml PBSand passed through a 0.45 μm filter (Minisart NML; Sartorius) to give afinal concentration of approximately 10¹³ transducing units/ml(ampicillin-resistant clones).

Panning of the Library. Immunotubes (Nunc) are coated overnight in PBSwith 4 ml of either 100 μg/ml or 10 μg/ml of a polypeptide of thepresent invention. Tubes are blocked with 2% Marvel-PBS for 2 hours at37° C. and then washed 3 times in PBS. Approximately 10¹³ TU of phage isapplied to the tube and incubated for 30 minutes at room temperaturetumbling on an over and under turntable and then left to stand foranother 1.5 hours. Tubes are washed 10 times with PBS 0.1% Tween-20 and10 times with PBS. Phage are eluted by adding 1 ml of 100 mMtriethylamine and rotating 15 minutes on an under and over turntableafter which the solution is immediately neutralized with 0.5 ml of 11.0MTris-HCl, pH 7.4. Phage are then used to infect 10 ml of mid-log E. coliTG1 by incubating eluted phage with bacteria for 30 minutes at 37° C.The E. coli are then plated on TYE plates containing 1% glucose and 100μg/ml ampicillin. The resulting bacterial library is then rescued withdelta gene 3 helper phage as described above to prepare phage for asubsequent round of selection. This process is then repeated for a totalof 4 rounds of affinity purification with tube-washing increased to 20times with PBS, 0.1% Tween-20 and 20 times with PBS for rounds 3 and 4.

Characterization of Binders. Eluted phage from the 3rd and 4th rounds ofselection are used to infect E. coli HB 2151 and soluble scFv isproduced (Marks, et al., 1991) from single colonies for assay. ELISAsare performed with microtitre plates coated with either 10 pg/ml of thepolypeptide of the present invention in 50 mM bicarbonate pH 9.6. Clonespositive in ELISA are further characterized by PCR fingerprinting (see,e.g., International Publication No. WO 92/01047) and then by sequencing.These ELISA positive clones may also be further characterized bytechniques known in the art, such as, for example, epitope mapping,binding affinity, receptor signal transduction, ability to block orcompetitively inhibit antibody/antigen binding, and competitiveagonistic or antagonistic activity.

Example 11 Method of Determining Alterations in a Gene Corresponding toa Polynucleotide

RNA isolated from entire families or individual patients presenting witha phenotype of interest (such as a disease) is isolated. cDNA is thengenerated from these RNA samples using protocols known in the art. (See,Sambrook.) The cDNA is then used as a template for PCR, employingprimers surrounding regions of interest in SEQ ID NO:X; and/or thenucleotide sequence of the cDNA contained in ATCC Deposit No: Z.Suggested PCR conditions consist of 35 cycles at 95 degrees C. for 30seconds; 60-120 seconds at 52-58 degrees C.; and 60-120 seconds at 70degrees C., using buffer solutions described in Sidransky et al.,Science 252:706 (1991).

PCR products are then sequenced using primers labeled at their 5′ endwith T4 polynucleotide kinase, employing SequiTherm Polymerase(Epicentre Technologies). The intron-exon boundaries of selected exonsis also determined and genomic PCR products analyzed to confirm theresults. PCR products harboring suspected mutations are then cloned andsequenced to validate the results of the direct sequencing.

PCR products are cloned into T-tailed vectors as described in Holton etal., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7polymerase (United States Biochemical). Affected individuals areidentified by mutations not present in unaffected individuals.

Genomic rearrangements are also observed as a method of determiningalterations in a gene corresponding to a polynucleotide. Genomic clonesisolated according to Example 2 are nick-translated withdigoxigenindeoxy-uridine 5′-triphosphate (Boehringer Manheim), and FISHperformed as described in Johnson et al., Methods Cell Biol. 35:73-99(1991). Hybridization with the labeled probe is carried out using a vastexcess of human cot-1 DNA for specific hybridization to thecorresponding genomic locus.

Chromosomes are counterstained with 4,6-diamino-2-phenylidole andpropidium iodide, producing a combination of C- and R-bands. Alignedimages for precise mapping are obtained using a triple-band filter set(Chroma Technology, Brattleboro, Vt.) in combination with a cooledcharge-coupled device camera (Photometrics, Tucson, Ariz.) and variableexcitation wavelength filters. (Johnson et al., Genet. Anal. Tech.Appl., 8:75 (1991)). Image collection, analysis and chromosomalfractional length measurements are performed using the ISee GraphicalProgram System. (Inovision Corporation, Durham, N.C.) Chromosomealterations of the genomic region hybridized by the probe are identifiedas insertions, deletions, and translocations. These alterations are usedas a diagnostic marker for an associated disease.

Example 12 Method of Detecting Abnormal Levels of a Polypeptide in aBiological Sample

A polypeptide of the present invention can be detected in a biologicalsample, and if an increased or decreased level of the polypeptide isdetected, this polypeptide is a marker for a particular phenotype.Methods of detection are numerous, and thus, it is understood that oneskilled in the art can modify the following assay to fit theirparticular needs.

For example, antibody-sandwich ELISAs are used to detect polypeptides ina sample, preferably a biological sample. Wells of a microtiter plateare coated with specific antibodies, at a final concentration of 0.2 to10 ug/ml. The antibodies are either monoclonal or polyclonal and areproduced by the method described in Example 10. The wells are blocked sothat non-specific binding of the polypeptide to the well is reduced.

The coated wells are then incubated for >2 hours at RT with a samplecontaining the polypeptide. Preferably, serial dilutions of the sampleshould be used to validate results. The plates are then washed threetimes with deionized or distilled water to remove unbound polypeptide.

Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at aconcentration of 25-400 ng, is added and incubated for 2 hours at roomtemperature. The plates are again washed three times with deionized ordistilled water to remove unbound conjugate.

Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenylphosphate (NPP) substrate solution to each well and incubate 1 hour atroom temperature. Measure the reaction by a microtiter plate reader.Prepare a standard curve, using serial dilutions of a control sample,and plot polypeptide concentration on the X-axis (log scale) andfluorescence or absorbance of the Y-axis (linear scale). Interpolate theconcentration of the polypeptide in the sample using the standard curve.

Example 13 Formulation

The invention also provides methods of treatment and/or prevention ofdiseases or disorders (such as, for example, any one or more of thediseases or disorders disclosed herein) by administration to a subjectof an effective amount of a Therapeutic. By therapeutic is meantpolynucleotides or polypeptides of the invention (including fragmentsand variants), agonists or antagonists thereof, and/or antibodiesthereto, in combination with a pharmaceutically acceptable carrier type(e.g., a sterile carrier).

The Therapeutic will be formulated and dosed in a fashion consistentwith good medical practice, taking into account the clinical conditionof the individual patient (especially the side effects of treatment withthe Therapeutic alone), the site of delivery, the method ofadministration, the scheduling of administration, and other factorsknown to practitioners. The “effective amount” for purposes herein isthus determined by such considerations.

As a general proposition, the total pharmaceutically effective amount ofthe Therapeutic administered parenterally per dose will be in the rangeof about 1 ug/kg/day to 10 mg/kg/day of patient body weight, although,as noted above, this will be subject to therapeutic discretion. Morepreferably, this dose is at least 0.01 mg/kg/day, and most preferablyfor humans between about 0.01 and 1 mg/kg/day for the hormone. If givencontinuously, the Therapeutic is typically administered at a dose rateof about 1 ug/kg/hour to about 50 ug/kg/hour, either by 1-4 injectionsper day or by continuous subcutaneous infusions, for example, using amini-pump. An intravenous bag solution may also be employed. The lengthof treatment needed to observe changes and the interval followingtreatment for responses to occur appears to vary depending on thedesired effect.

Therapeutics can be are administered orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, gels, drops or transdermal patch), bucally, or as anoral or nasal spray. “Pharmaceutically acceptable carrier” refers to anon-toxic solid, semisolid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliary of any. The term “parenteral” as usedherein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

Therapeutics of the invention are also suitably administered bysustained-release systems. Suitable examples of sustained-releaseTherapeutics are administered orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, gels, drops or transdermal patch), bucally, or as anoral or nasal spray. “Pharmaceutically acceptable carrier” refers to anon-toxic solid, semisolid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliary of any type. The term “parenteral” asused herein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

Therapeutics of the invention are also suitably administered bysustained-release systems. Suitable examples of sustained-releaseTherapeutics include suitable polymeric materials (such as, for example,semi-permeable polymer matrices in the form of shaped articles, e.g.,films, or mirocapsules), suitable hydrophobic materials (for example asan emulsion in an acceptable oil) or ion exchange resins, and sparinglysoluble derivatives (such as, for example, a sparingly soluble salt).

Sustained-release matrices include polylactides (U.S. Pat. No.3,773,919, EP 58,481), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547-556 (1983)),poly (2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater.Res. 15:167-277 (1981), and Langer, Chem. Tech. 12:98-105 (1982)),ethylene vinyl acetate (Langer et al., Id.) orpoly-D-(−)-3-hydroxybutyric acid (EP 133,988).

In a preferred embodiment, polypeptide, polynucleotide, and antibodycompositions of the invention are formulated in a biodegradable,polymeric drug delivery system, for example as described in U.S. Pat.Nos. 4,938,763; 5,278,201; 5,278,202; 5,324,519; 5,340,849; and5,487,897 and in International Publication Numbers WO01/35929,WO00/24374, and WO00/06117 which are hereby incorporated by reference intheir entirety. In specific preferred embodiments the polypeptide,polynucleotide, and antibody compositions of the invention areformulated using the ATRIGEL® Biodegradable System of AtrixLaboratories, Inc. (Fort Collins, Colo.).

Examples of biodegradable polymers which can be used in the formulationof polypeptide, polynucleotide, and antibody compositions, include butare not limited to, polylactides, polyglycolides, polycaprolactones,polyanhydrides, polyamides, polyurethanes, polyesteramides,polyorthoesters, polydioxanones, polyacetals, polyketals,polycarbonates, polyorthocarbonates, polyphosphazenes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids),poly(methyl vinyl ether), poly(maleic anhydride), polyvinylpyrrolidone,polyethylene glycol, polyhydroxycellulose, chitin, chitosan, andcopolymers, terpolymers, or combinations or mixtures of the abovematerials. The preferred polymers are those that have a lower degree ofcrystallization and are more hydrophobic. These polymers and copolymersare more soluble in the biocompatible solvents than the highlycrystalline polymers such as polyglycolide and chitin which also have ahigh degree of hydrogen-bonding. Preferred materials with the desiredsolubility parameters are the polylactides, polycaprolactones, andcopolymers of these with glycolide in which there are more amorphousregions to enhance solubility. In specific preferred embodiments, thebiodegradable polymers which can be used in the formulation ofpolypeptide, polynucleotide, and antibody compositions arepoly(lactide-co-glycolides). Polymer properties such as molecularweight, hydrophobicity, and lactide/glycolide ratio may be modified toobtain the desired polypeptide, polynucleotide, or antibody releaseprofile (See, e.g., Ravivarapu et al., Journal of PharmaceuticalSciences 89:732-741 (2000), which is hereby incorporated by reference inits entirety).

It is also preferred that the solvent for the biodegradable polymer benon-toxic, water miscible, and otherwise biocompatible. Examples of suchsolvents include, but are not limited to, N-methyl-2-pyrrolidone,2-pyrrolidone, C2 to C6 alkanols, C1 to C15 alchohols, dils, triols, andtetraols such as ethanol, glycerine propylene glycol, butanol; C3 to C15alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone;C3 to C15 esters such as methyl acetate, ethyl acetate, ethyl lactate;alkyl ketones such as methyl ethyl ketone, C1 to C15 amides such asdimethylformamide, dimethylacetamide and caprolactam; C3 to C20 etherssuch as tetrahydrofuran, or solketal; tweens, triacetin, propylenecarbonate, decylmethylsulfoxide, dimethyl sulfoxide, oleic acid,1-dodecylazacycloheptan-2-one, Other preferred solvents are benzylalchohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate,glycerin, glycofural, isopropyl myristate, isopropyl palmitate, oleicacid, polyethylene glycol, propylene carbonate, and triethyl citrate.The most preferred solvents are N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethyl sulfoxide, triacetin, and propylene carbonate because of thesolvating ability and their compatibility.

Additionally, formulations comprising polypeptide, polynucleotide, andantibody compositions and a biodegradable polymer may also includerelease-rate modification agents and/or pore-forming agents. Examples ofrelease-rate modification agents include, but are not limited to, fattyacids, triglycerides, other like hydrophobic compounds, organicsolvents, plasticizing compounds and hydrophilic compounds. Suitablerelease rate modification agents include, for example, esters of mono-,di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, methylacetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutylphthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate,dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyltriethyl citrate, glycerol triacetate, di(n-butyl) sebecate, and thelike; polyhydroxy alcohols, such as propylene glycol, polyethyleneglycol, glycerin, sorbitol, and the like; fatty acids; triesters ofglycerol, such as triglycerides, epoxidized soybean oil, and otherepoxidized vegetable oils; sterols, such as cholesterol; alcohols, suchas C.sub.6-C.sub.12 alkanols, 2-ethoxyethanol. The release ratemodification agent may be used singly or in combination with other suchagents. Suitable combinations of release rate modification agentsinclude, but are not limited to, glycerin/propylene glycol,sorbitol/glycerine, ethylene oxide/propylene oxide, butyleneglycol/adipic acid, and the like. Preferred release rate modificationagents include, but are not limited to, dimethyl citrate, triethylcitrate, ethyl heptanoate, glycerin, and hexanediol. Suitablepore-forming agents that may be used in the polymer composition include,but are not limited to, sugars such as sucrose and dextrose, salts suchas sodium chloride and sodium carbonate, polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol,and polyvinylpyrrolidone. Solid crystals that will provide a definedpore size, such as salt or sugar, are preferred.

In specific preferred embodiments the polypeptide, polynucleotide, andantibody compositions of the invention are formulated using the BEMA™BioErodible Mucoadhesive System, MCA™ MucoCutaneous Absorption System,SMP™ Solvent MicroParticle System, or BCP™ BioCompatible Polymer Systemof Atrix Laboratories, Inc. (Fort Collins, Colo.).

Sustained-release Therapeutics also include liposomally entrappedTherapeutics of the invention (see generally, Langer, Science249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy ofInfectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss,New York, pp. 317-327 and 353-365 (1989)). Liposomes containing theTherapeutic are prepared by methods known per se: DE 3,218,121; Epsteinet al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al.,Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP 52,322; EP 36,676;EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S.Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, theliposomes are of the small (about 200-800 Angstroms) unilamellar type inwhich the lipid content is greater than about 30 mol. percentcholesterol, the selected proportion being adjusted for the optimalTherapeutic.

In yet an additional embodiment, the Therapeutics of the invention aredelivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref.Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980);Saudek et al., N. Engl. J. Med. 321:574 (1989)).

Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)).

For parenteral administration, in one embodiment, the Therapeutic isformulated generally by mixing it at the desired degree of purity, in aunit dosage injectable form (solution, suspension, or emulsion), with apharmaceutically acceptable carrier, i.e., one that is non-toxic torecipients at the dosages and concentrations employed and is compatiblewith other ingredients of the formulation. For example, the formulationpreferably does not include oxidizing agents and other compounds thatare known to be deleterious to the Therapeutic.

Generally, the formulations are prepared by contacting the Therapeuticuniformly and intimately with liquid carriers or finely divided solidcarriers or both. Then, if necessary, the product is shaped into thedesired formulation. Preferably the carrier is a parenteral carrier,more preferably a solution that is isotonic with the blood of therecipient. Examples of such carrier vehicles include water, saline,Ringer's solution, and dextrose solution. Non-aqueous vehicles such asfixed oils and ethyl oleate are also useful herein, as well asliposomes.

The carrier suitably contains minor amounts of additives such assubstances that enhance isotonicity and chemical stability. Suchmaterials are non-toxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate, succinate,acetic acid, and other organic acids or their salts; antioxidants suchas ascorbic acid; low molecular weight (less than about ten residues)polypeptides, e.g., polyarginine or tripeptides; proteins, such as serumalbumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids, such as glycine, glutamic acid,aspartic acid, or arginine; monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, manose,or dextrins; chelating agents such as EDTA; sugar alcohols such asmannitol or sorbitol; counterions such as sodium; and/or nonionicsurfactants such as polysorbates, poloxamers, or PEG.

The Therapeutic is typically formulated in such vehicles at aconcentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, ata pH of about 3 to 8. It will be understood that the use of certain ofthe foregoing excipients, carriers, or stabilizers will result in theformation of polypeptide salts.

Any pharmaceutical used for therapeutic administration can be sterile.Sterility is readily accomplished by filtration through sterilefiltration membranes (e.g., 0.2 micron membranes). Therapeuticsgenerally are placed into a container having a sterile access port, forexample, an intravenous solution bag or vial having a stopper pierceableby a hypodermic injection needle.

Therapeutics ordinarily will be stored in unit or multi-dose containers,for example, sealed ampoules or vials, as an aqueous solution or as alyophilized formulation for reconstitution. As an example of alyophilized formulation, 10-ml vials are filled with 5 ml ofsterile-filtered 1% (w/v) aqueous Therapeutic solution, and theresulting mixture is lyophilized. The infusion solution is prepared byreconstituting the lyophilized Therapeutic using bacteriostaticWater-for-Injection.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of theTherapeutics of the invention. Associated with such container(s) can bea notice in the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration. In addition, the Therapeutics may be employedin conjunction with other therapeutic compounds.

The Therapeutics of the invention may be administered alone or incombination with adjuvants. Adjuvants that may be administered with theTherapeutics of the invention include, but are not limited to, alum,alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21(Genentech, Inc.), BCG (e.g., THERACYS®), MPL and nonviable prepartionsof Corynebacterium parvum. In a specific embodiment, Therapeutics of theinvention are administered in combination with alum. In another specificembodiment, Therapeutics of the invention are administered incombination with QS-21. Further adjuvants that may be administered withthe Therapeutics of the invention include, but are not limited to,Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18,CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology.Vaccines that may be administered with the Therapeutics of the inventioninclude, but are not limited to, vaccines directed toward protectionagainst MMR (measles, mumps, rubella), polio, varicella,tetanus/diptheria, hepatitis A, hepatitis B, haemophilus influenzae B,whooping cough, pneumonia, influenza, Lyme's Disease, rotavirus,cholera, yellow fever, Japanese encephalitis, poliomyelitis, rabies,typhoid fever, and pertussis. Combinations may be administered eitherconcomitantly, e.g., as an admixture, separately but simultaneously orconcurrently; or sequentially. This includes presentations in which thecombined agents are administered together as a therapeutic mixture, andalso procedures in which the combined agents are administered separatelybut simultaneously, e.g., as through separate intravenous lines into thesame individual. Administration “in combination” further includes theseparate administration of one of the compounds or agents given first,followed by the second.

The Therapeutics of the invention may be administered alone or incombination with other therapeutic agents. Therapeutic agents that maybe administered in combination with the Therapeutics of the invention,include but not limited to, chemotherapeutic agents, antibiotics,steroidal and non-steroidal anti-inflammatories, conventionalimmunotherapeutic agents, and/or therapeutic treatments described below.Combinations may be administered either concomitantly, e.g., as anadmixture, separately but simultaneously or concurrently; orsequentially. This includes presentations in which the combined agentsare administered together as a therapeutic mixture, and also proceduresin which the combined agents are administered separately butsimultaneously, e.g., as through separate intravenous lines into thesame individual. Administration “in combination” further includes theseparate administration of one of the compounds or agents given first,followed by the second.

In one embodiment, the Therapeutics of the invention are administered incombination with an anticoagulant. Anticoagulants that may beadministered with the compositions of the invention include, but are notlimited to, heparin, low molecular weight heparin, warfarin sodium(e.g., COUMADIN®), dicumarol, 4-hydroxycoumarin, anisindione (e.g.,MIRADON™), acenocoumarol (e.g., nicoumalone, SINTHROME™),indan-1,3-dione, phenprocoumon (e.g., MARCUMAR™), ethyl biscoumacetate(e.g., TROMEXAN™), and aspirin. In a specific embodiment, compositionsof the invention are administered in combination with heparin and/orwarfarin. In another specific embodiment, compositions of the inventionare administered in combination with warfarin. In another specificembodiment, compositions of the invention are administered incombination with warfarin and aspirin. In another specific embodiment,compositions of the invention are administered in combination withheparin. In another specific embodiment, compositions of the inventionare administered in combination with heparin and aspirin.

In another embodiment, the Therapeutics of the invention areadministered in combination with thrombolytic drugs. Thrombolytic drugsthat may be administered with the compositions of the invention include,but are not limited to, plasminogen, lys-plasminogen,alpha2-antiplasmin, streptokinae (e.g., KABIKINASE™), antiresplace(e.g., EMINASE™), tissue plasminogen activator (t-PA, altevase,ACTIVASE™), urokinase (e.g., ABBOKINASE™), sauruplase, (Prourokinase,single chain urokinase), and aminocaproic acid (e.g., AMICAR™). In aspecific embodiment, compositions of the invention are administered incombination with tissue plasminogen activator and aspirin.

In another embodiment, the Therapeutics of the invention areadministered in combination with antiplatelet drugs. Antiplatelet drugsthat may be administered with the compositions of the invention include,but are not limited to, aspirin, dipyridamole (e.g., PERSANTINE™), andticlopidine (e.g., TICLID™).

In specific embodiments, the use of anti-coagulants, thrombolytic and/orantiplatelet drugs in combination with Therapeutics of the invention iscontemplated for the prevention, diagnosis, and/or treatment ofthrombosis, arterial thrombosis, venous thrombosis, thromboembolism,pulmonary embolism, atherosclerosis, myocardial infarction, transientischemic attack, unstable angina. In specific embodiments, the use ofanticoagulants, thrombolytic drugs and/or antiplatelet drugs incombination with Therapeutics of the invention is contemplated for theprevention of occulsion of saphenous grafts, for reducing the risk ofperiprocedural thrombosis as might accompany angioplasty procedures, forreducing the risk of stroke in patients with atrial fibrillationincluding nonrheumatic atrial fibrillation, for reducing the risk ofembolism associated with mechanical heart valves and or mitral valvesdisease. Other uses for the therapeutics of the invention, alone or incombination with antiplatelet, anticoagulant, and/or thrombolytic drugs,include, but are not limited to, the prevention of occlusions inextracorporeal devices (e.g., intravascular canulas, vascular accessshunts in hemodialysis patients, hemodialysis machines, andcardiopulmonary bypass machines).

In certain embodiments, Therapeutics of the invention are administeredin combination with antiretroviral agents, nucleoside/nucleotide reversetranscriptase inhibitors (NRTIs), non-nucleoside reverse transcriptaseinhibitors (NNRTIs), and/or protease inhibitors (PIs). NRTIs that may beadministered in combination with the Therapeutics of the invention,include, but are not limited to, RETROVIR™ (zidovudine/AZT), VIDEX™(didanosine/ddI), HIVID™ (zalcitabine/ddC), ZERIT™ (stavudine/d4T),EPIVIR™ (larnivudine/3TC), and COMBIVIR™ (zidovudine/lamivudine). NNRTIsthat may be administered in combination with the Therapeutics of theinvention, include, but are not limited to, VIRAMUNE™ (nevirapine),RESCRIPTOR™ (delavirdine), and SUSTIVA™ (efavirenz). Protease inhibitorsthat may be administered in combination with the Therapeutics of theinvention, include, but are not limited to, CRIXIVAN™ (indinavir),NORVIR™ (ritonavir), INVIRASE™ (saquinavir), and VICEPT™ (nelfinavir).In a specific embodiment, antiretroviral agents, nucleoside reversetranscriptase inhibitors, non-nucleoside reverse transcriptaseinhibitors, and/or protease inhibitors may be used in any combinationwith Therapeutics of the invention to treat AIDS and/or to prevent ortreat HIV infection.

Additional NRTIs include LODENOSINE™ (F-ddA; an acid-stable adenosineNRTI; Triangle/Abbott; COVIRACIL™ (emtricitabine/FTC; structurallyrelated to lamivudine (3TC) but with 3- to 10-fold greater activity invitro; Triangle/Abbott); dOTC (BCH-10652, also structurally related tolamivudine but retains activity against a substantial proportion oflamivudine-resistant isolates; Biochem Pharma); Adefovir (refusedapproval for anti-HIV therapy by FDA; Gilead Sciences); PREVEON®(Adefovir Dipivoxil, the active prodrug of adefovir; its active form isPMEA-pp); TENOFOVIR™ (bis-POC PMPA, a PMPA prodrug; Gilead); DAPD/DXG(active metabolite of DAPD; Triangle/Abbott); D-D4FC (related to 3TC,with activity against AZT/3TC-resistant virus); GW420867X (GlaxoWellcome); ZIAGEN™ (abacavir/159 U89; Glaxo Wellcome Inc.); CS-87(3′azido-2′,3′-dideoxyuridine; WO 99/66936); and S-acyl-2-thioethyl(SATE)-bearing prodrug forms of β-L-FD4C and β-L-FddC (WO 98/17281).

Additional NNRTIs include COACTINON™ (Emivirine/MKC-442, potent NNRTI ofthe HEPT class; Triangle/Abbott); CAPRAVIRINE™ (AG-1549/S-1153, a nextgeneration NNRTI with activity against viruses containing the K103Nmutation, Agouron); PNU-142721 (has 20- to 50-fold greater activity thanits predecessor delavirdine and is active against K103N mutants;Pharmacia & Upjohn); DPC-961 and DPC-963 (second-generation derivativesof efavirenz, designed to be active against viruses with the K103Nmutation; DuPont); GW-420867× (has 25-fold greater activity than HBY097and is active against K103N mutants; Glaxo Wellcome); CALANOLIDE A(naturally occurring agent from the latex tree; active against virusescontaining either or both the Y181C and K103N mutations); and Propolis(WO 99/49830).

Additional protease inhibitors include LOPINAVIR™ (ABT378/r; AbbottLaboratories); BMS-232632 (an azapeptide; Bristol-Myres Squibb);TIPRANAVIR™ (PNU-140690, a non-peptic dihydropyrone; Pharmacia &Upjohn); PD-178390 (a nonpeptidic dihydropyrone; Parke-Davis); BMS232632 (an azapeptide; Bristol-Myers Squibb); L-756,423 (an indinaviranalog; Merck); DMP-450 (a cyclic urea compound; Avid & DuPont); AG-1776(a peptidomimetic with in vitro activity against proteaseinhibitor-resistant viruses; Agouron); VX-175/GW-433908 (phosphateprodrug of amprenavir; Vertex & Glaxo Welcome); CGP61755 (Ciba); andAGENERASE™ (amprenavir; Glaxo Wellcome Inc.).

Additional antiretroviral agents include fusion inhibitors/gp41 binders.Fusion inhibitors/gp41 binders include T-20 (a peptide from residues643-678 of the HIV gp41 transmembrane protein ectodomain which binds togp41 in its resting state and prevents transformation to the fusogenicstate; Trimeris) and T-1249 (a second-generation fusion inhibitor;Trimeris).

Additional antiretroviral agents include fusion inhibitors/chemokinereceptor antagonists. Fusion inhibitors/chemokine receptor antagonistsinclude CXCR4 antagonists such as AMD 3100 (a bicyclam), SDF-1 and itsanalogs, and ALX40-4C (a cationic peptide), T22 (an 18 amino acidpeptide; Trimeris) and the T22 analogs T134 and T140; CCR5 antagonistssuch as RANTES (9-68), AOP-RANTES, NNY-RANTES, and TAK-779; andCCR5/CXCR4 antagonists such as NSC 651016 (a distamycin analog). Alsoincluded are CCR2B, CCR3, and CCR6 antagonists. Chemokine recpetoragonists such as RANTES, SDF-1, MIP-1α, MIP-1β, etc., may also inhibitfusion.

Additional antiretroviral agents include integrase inhibitors. Integraseinhibitors include dicaffeoylquinic (DFQA) acids; L-chicoric acid (adicaffeoyltartaric (DCTA) acid); quinalizarin (QLC) and relatedanthraquinones; ZINTEVIR™ (AR 177, an oligonucleotide that probably actsat cell surface rather than being a true integrase inhibitor; Arondex);and naphthols such as those disclosed in WO 98/50347.

Additional antiretroviral agents include hydroxyurea-like compounds suchas BCX-34 (a purine nucleoside phosphorylase inhibitor; Biocryst);ribonucleotide reductase inhibitors such as DIDOX™ (Molecules forHealth); inosine monophosphate dehydrogenase (IMPDH) inhibitors sucha asVX-497 (Vertex); and mycopholic acids such as CellCept (mycophenolatemofetil; Roche).

Additional antiretroviral agents include inhibitors of viral integrase,inhibitors of viral genome nuclear translocation such as arylenebis(methylketone) compounds; inhibitors of HIV entry such as AOP-RANTES,NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES andglycosaminoglycans (GAG), and AMD-3100; nucleocapsid zinc fingerinhibitors such as dithiane compounds; targets of HIV Tat and Rev; andpharmacoenhancers such as ABT-378.

Other antiretroviral therapies and adjunct therapies include cytokinesand lymphokines such as MIP-1α, MIP-1β, SDF-1α, IL-2, PROLEUKIN™(aldesleukin/L2-7001; Chiron), IL-4, IL-10, IL-12, and IL-13;interferons such as IFN-α2a; antagonists of TNFs, NFκB, GM-CSF, M-CSF,and IL-10; agents that modulate immune activation such as cyclosporinand prednisone; vaccines such as Remune™ (HIV Immunogen), APL 400-003(Apollon), recombinant gp120 and fragments, bivalent (B/E) recombinantenvelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120,gp120/soluble CD4 complex, Delta JR-FL protein, branched syntheticpeptide derived from discontinuous gp120 C3/C4 domain, fusion-competentimmunogens, and Gag, Pol, Nef, and Tat vaccines; gene-based therapiessuch as genetic suppressor elements (GSEs; WO 98/54366), and intrakines(genetically modified CC chemokines targetted to the ER to block surfaceexpression of newly synthesized CCR5 (Yang et al., PNAS 94:11567-72(1997); Chen et al., Nat. Med. 3:1110-16 (1997)); antibodies such as theanti-CXCR4 antibody 12G5, the anti-CCR5 antibodies 2D7, 5C7, PA8, PA9,PA10, PA11, PA12, and PA14, the anti-CD4 antibodies Q4120 and RPA-T4,the anti-CCR3 antibody 7B11, the anti-gp120 antibodies 17b, 48d,447-52D, 257-D, 268-D and 50.1, anti-Tat antibodies, anti-TNF-αantibodies, and monoclonal antibody 33A; aryl hydrocarbon (AH) receptoragonists and antagonists such as TCDD, 3,3′,4,4′,5-pentachlorobiphenyl,3,3′,4,4′-tetrachlorobiphenyl, and α-naphthoflavone (WO 98/30213); andantioxidants such as γ-L-glutamyl-L-cysteine ethyl ester (γ-GCE; WO99/56764).

In a further embodiment, the Therapeutics of the invention areadministered in combination with an antiviral agent. Antiviral agentsthat may be administered with the Therapeutics of the invention include,but are not limited to, acyclovir, ribavirin, amantadine, andremantidine.

In other embodiments, Therapeutics of the invention may be administeredin combination with anti-opportunistic infection agents.Anti-opportunistic agents that may be administered in combination withthe Therapeutics of the invention, include, but are not limited to,TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, ATOVAQUONE™,ISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, ETHAMBUTOL™, RIFABUTIN™,CLARITHROMYCIN™, AZITHROMYCIN™, GANCICLOVIR™, FOSCARNET™, CIDOFOVIR™,FLUCONAZOLE™, ITRACONAZOLE™, KETOCONAZOLE™, ACYCLOVIR™, FAMCICOLVIR™,PYRIMETHAMINE™, LEUCOVORIN™, NEUPOGEN™ (filgrastim/G-CSF), and LEUKINE™(sargramostim/GM-CSF). In a specific embodiment, Therapeutics of theinvention are used in any combination withTRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, and/orATOVAQUONE™ to prophylactically treat or prevent an opportunisticPneumocystis carinii pneumonia infection. In another specificembodiment, Therapeutics of the invention are used in any combinationwith ISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, and/or ETHAMBUTOL™ toprophylactically treat or prevent an opportunistic Mycobacterium aviumcomplex infection. In another specific embodiment, Therapeutics of theinvention are used in any combination with RIFABUTIN™, CLARITHROMYCIN™,and/or AZITHROMYCIN™ to prophylactically treat or prevent anopportunistic Mycobacterium tuberculosis infection. In another specificembodiment, Therapeutics of the invention are used in any combinationwith GANCICLOVIR™, FOSCARNET™, and/or CIDOFOVIR™ to prophylacticallytreat or prevent an opportunistic cytomegalovirus infection. In anotherspecific embodiment, Therapeutics of the invention are used in anycombination with FLUCONAZOLE™, ITRACONAZOLE™, and/or KETOCONAZOLE™ toprophylactically treat or prevent an opportunistic fungal infection. Inanother specific embodiment, Therapeutics of the invention are used inany combination with ACYCLOVIR™ and/or FAMCICOLVIR™ to prophylacticallytreat or prevent an opportunistic herpes simplex virus type I and/ortype II infection. In another specific embodiment, Therapeutics of theinvention are used in any combination with PYRIMETHAMINE™ and/orLEUCOVORIN™ to prophylactically treat or prevent an opportunisticToxoplasma gondii infection. In another specific embodiment,Therapeutics of the invention are used in any combination withLEUCOVORIN™ and/or NEUPOGEN™ to prophylactically treat or prevent anopportunistic bacterial infection.

In a further embodiment, the Therapeutics of the invention areadministered in combination with an antibiotic agent. Antibiotic agentsthat may be administered with the Therapeutics of the invention include,but are not limited to, amoxicillin, beta-lactamases, aminoglycosides,beta-lactam (glycopeptide), beta-lactamases, Clindamycin,chloramphenicol, cephalosporins, ciprofloxacin, erythromycin,fluoroquinolones, macrolides, metronidazole, penicillins, quinolones,rapamycin, rifampin, streptomycin, sulfonamide, tetracyclines,trimethoprim, trimethoprim-sulfamethoxazole, and vancomycin.

In other embodiments, the Therapeutics of the invention are administeredin combination with immunestimulants. Immunostimulants that may beadministered in combination with the Therapeutics of the inventioninclude, but are not limited to, levamisole (e.g., ERGAMISOL™),isoprinosine (e.g. INOSIPLEX™), interferons (e.g. interferon alpha), andinterleukins (e.g., IL-2).

In other embodiments, Therapeutics of the invention are administered incombination with immunosuppressive agents. Immunosuppressive agents thatmay be administered in combination with the Therapeutics of theinvention include, but are not limited to, steroids, cyclosporine,cyclosporine analogs, cyclophosphamide methylprednisone, prednisone,azathioprine, FK-506, 15-deoxyspergualin, and other immunosuppressiveagents that act by suppressing the function of responding T cells. Otherimmunosuppressive agents that may be administered in combination withthe Therapeutics of the invention include, but are not limited to,prednisolone, methotrexate, thalidomide, methoxsalen, rapamycin,leflunomide, mizoribine (BREDININ™), brequinar, deoxyspergualin, andazaspirane (SKF 105685), ORTHOCLONE OKT® 3 (muromonab-CD3), SANDIMMUNE™,NEORAL™, SANGDYA™ (cyclosporine), PROGRAF® (FK506, tacrolimus),CELLCEPT® (mycophenolate motefil, of which the active metabolite ismycophenolic acid), IMURAN™ (azathioprine), glucocorticosteroids,adrenocortical steroids such as DELTASONE™ (prednisone) and HYDELTRASOL™(prednisolone), FOLEX™ and MEXATE™ (methotrxate), OXSORALEN-ULTRA™(methoxsalen) and RAPAMUNE™ (sirolimus). In a specific embodiment,immunosuppressants may be used to prevent rejection of organ or bonemarrow transplantation.

In an additional embodiment, Therapeutics of the invention areadministered alone or in combination with one or more intravenous immuneglobulin preparations. Intravenous immune globulin preparations that maybe administered with the Therapeutics of the invention include, but notlimited to, GAMMAR™, IVEEGAM™, SANDOGLOBULIN™, GAMMAGARD S/D™, ATGAM™(antithymocyte glubulin), and GAMIMUNE™. In a specific embodiment,Therapeutics of the invention are administered in combination withintravenous immune globulin preparations in transplantation therapy(e.g., bone marrow transplant).

In certain embodiments, the Therapeutics of the invention areadministered alone or in combination with an anti-inflammatory agent.Anti-inflammatory agents that may be administered with the Therapeuticsof the invention include, but are not limited to, corticosteroids (e.g.betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone,methylprednisolone, prednisolone, prednisone, and triamcinolone),nonsteroidal anti-inflammatory drugs (e.g., diclofenac, diflunisal,etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen,indomethacin, ketoprofen, meclofenamate, mefenamic acid, meloxicam,nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac,tenoxicam, tiaprofenic acid, and tolmetin.), as well as antihistamines,aminoarylcarboxylic acid derivatives, arylacetic acid derivatives,arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acidderivatives, pyrazoles, pyrazolones, salicylic acid derivatives,thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine,3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine,bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone,nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime,proquazone, proxazole, and tenidap.

In an additional embodiment, the compositions of the invention areadministered alone or in combination with an anti-angiogenic agent.Anti-angiogenic agents that may be administered with the compositions ofthe invention include, but are not limited to, Angiostatin (Entremed,Rockville, Md.), Troponin-1 (Boston Life Sciences, Boston, Mass.),anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel(Taxol), Suramin, Tissue Inhibitor of Metalloproteinase-1, TissueInhibitor of Metalloproteinase-2, VEGI, Plasminogen ActivatorInhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of thelighter “d group” transition metals.

Lighter “d group” transition metals include, for example, vanadium,molybdenum, tungsten, titanium, niobium, and tantalum species. Suchtransition metal species may form transition metal complexes. Suitablecomplexes of the above-mentioned transition metal species include oxotransition metal complexes.

Representative examples of vanadium complexes include oxo vanadiumcomplexes such as vanadate and vanadyl complexes. Suitable vanadatecomplexes include metavanadate and orthovanadate complexes such as, forexample, ammonium metavanadate, sodium metavanadate, and sodiumorthovanadate. Suitable vanadyl complexes include, for example, vanadylacetylacetonate and vanadyl sulfate including vanadyl sulfate hydratessuch as vanadyl sulfate mono- and trihydrates.

Representative examples of tungsten and molybdenum complexes alsoinclude oxo complexes. Suitable oxo tungsten complexes include tungstateand tungsten oxide complexes. Suitable tungstate complexes includeammonium tungstate, calcium tungstate, sodium tungstate dihydrate, andtungstic acid. Suitable tungsten oxides include tungsten (IV) oxide andtungsten (VI) oxide. Suitable oxo molybdenum complexes includemolybdate, molybdenum oxide, and molybdenyl complexes. Suitablemolybdate complexes include ammonium molybdate and its hydrates, sodiummolybdate and its hydrates, and potassium molybdate and its hydrates.Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum(VI) oxide, and molybdic acid. Suitable molybdenyl complexes include,for example, molybdenyl acetylacetonate. Other suitable tungsten andmolybdenum complexes include hydroxo derivatives derived from, forexample, glycerol, tartaric acid, and sugars.

A wide variety of other anti-angiogenic factors may also be utilizedwithin the context of the present invention. Representative examplesinclude, but are not limited to, platelet factor 4; protamine sulphate;sulphated chitin derivatives (prepared from queen crab shells), (Murataet al., Cancer Res. 51:22-26, (1991)); Sulphated PolysaccharidePeptidoglycan Complex (SP-PG) (the function of this compound may beenhanced by the presence of steroids such as estrogen, and tamoxifencitrate); Staurosporine; modulators of matrix metabolism, including forexample, proline analogs, cishydroxyproline, d,L-3,4-dehydroproline,Thiaproline, alpha,alpha-dipyridyl, aminopropionitrile fumarate;4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Methotrexate; Mitoxantrone;Heparin; Interferons; 2 Macroglobulin-serum; ChIMP-3 (Pavloff et al., J.Bio. Chem. 267:17321-17326, (1992)); Chymostatin (Tomkinson et al.,Biochem J. 286:475-480, (1992)); Cyclodextrin Tetradecasulfate;Eponemycin; Camptothecin; Fumagillin (Ingber et al., Nature 348:555-557,(1990)); Gold Sodium Thiomalate (“GST”; Matsubara and Ziff, J. Clin.Invest. 79:1440-1446, (1987)); anticollagenase-serum; alpha2-antiplasmin(Holmes et al., J. Biol. Chem. 262(4):1659-1664, (1987)); Bisantrene(National Cancer Institute); Lobenzarit disodium(N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”;(Takeuchi et al., Agents Actions 36:312-316, (1992)); andmetalloproteinase inhibitors such as BB94.

Additional anti-angiogenic factors that may also be utilized within thecontext of the present invention include Thalidomide, (Celgene, Warren,N.J.); Angiostatic steroid; AGM-1470 (H. Brem and J. Folkman J Pediatr.Surg. 28:445-51 (1993)); an integrin alpha v beta 3 antagonist (C.Storgard et al., J. Clin. Invest. 103:47-54 (1999));carboxynaminolmidazole; Carboxyamidotriazole (CAI) (National CancerInstitute, Bethesda, Md.); Conbretastatin A-4 (CA4P) (OXiGENE, Boston,Mass.); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pa.);TNP-470, (Tap Pharmaceuticals, Deerfield, Ill.); ZD-0101 AstraZeneca(London, UK); APRA (CT2584); Benefin, Byrostatin-1 (SC339555); CGP-41251(PKC 412); CM11; Dexrazoxane (ICRF187); DMXAA; Endostatin; Flavopridiol;Genestein; GTE; ImmTher; Iressa (ZD1839); Octreotide (Somatostatin);Panretin; Penacillamine; Photopoint; PI-88; Prinomastat (AG-3340)Purlytin; Suradista (FCE26644); Tamoxifen (Nolvadex); Tazarotene;Tetrathiomolybdate; Xeloda (Capecitabine); and 5-Fluorouracil.

Anti-angiogenic agents that may be administed in combination with thecompounds of the invention may work through a variety of mechanismsincluding, but not limited to, inhibiting proteolysis of theextracellular matrix, blocking the function of endothelialcell-extracellular matrix adhesion molecules, by antagonizing thefunction of angiogenesis inducers such as growth factors, and inhibitingintegrin receptors expressed on proliferating endothelial cells.Examples of anti-angiogenic inhibitors that interfere with extracellularmatrix proteolysis and which may be administered in combination with thecompositons of the invention include, but are not lmited to, AG-3340(Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer, West Haven, Conn.),BMS-275291 (Bristol Myers Squibb, Princeton, N.J.), CGS-27032A(Novartis, East Hanover, N.J.), Marimastat (British Biotech, Oxford,UK), and Metastat (Aetema, St-Foy, Quebec). Examples of anti-angiogenicinhibitors that act by blocking the function of endothelialcell-extracellular matrix adhesion molecules and which may beadministered in combination with the compositons of the inventioninclude, but are not limited to, EMD-121974 (Merck KcgaA Darmstadt,Germany) and Vitaxin (Ixsys, La Jolla, Calif./Medimmune, Gaithersburg,Md.). Examples of anti-angiogenic agents that act by directlyantagonizing or inhibiting angiogenesis inducers and which may beadministered in combination with the compositons of the inventioninclude, but are not lmited to, Angiozyme (Ribozyme, Boulder, Colo.),Anti-VEGF antibody (Genentech, S. San Francisco, Calif.),PTK-787/ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. SanFrancisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.),and SU-6668 (Sugen). Other anti-angiogenic agents act to indirectlyinhibit angiogenesis. Examples of indirect inhibitors of angiogenesiswhich may be administered in combination with the compositons of theinvention include, but are not limited to, IM-862 (Cytran, Kirkland,Wash.), Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosanpolysulfate (Georgetown University, Washington, D.C.).

In particular embodiments, the use of compositions of the invention incombination with anti-angiogenic agents is contemplated for thetreatment, prevention, and/or amelioration of an autoimmune disease,such as for example, an autoimmune disease described herein.

In a particular embodiment, the use of compositions of the invention incombination with anti-angiogenic agents is contemplated for thetreatment, prevention, and/or amelioration of arthritis. In a moreparticular embodiment, the use of compositions of the invention incombination with anti-angiogenic agents is contemplated for thetreatment, prevention, and/or amelioration of rheumatoid arthritis.

In another embodiment, the polynucleotides encoding a polypeptide of thepresent invention are administered in combination with an angiogenicprotein, or polynucleotides encoding an angiogenic protein. Examples ofangiogenic proteins that may be administered with the compositions ofthe invention include, but are not limited to, acidic and basicfibroblast growth factors, VEGF-1, VEGF-2, VEGF-3, epidermal growthfactor alpha and beta, platelet-derived endothelial cell growth factor,platelet-derived growth factor, tumor necrosis factor alpha, hepatocytegrowth factor, insulin-like growth factor, colony stimulating factor,macrophage colony stimulating factor, granulocyte/macrophage colonystimulating factor, and nitric oxide synthase.

In additional embodiments, compositions of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents that may be administered with the Therapeuticsof the invention include, but are not limited to alkylating agents suchas nitrogen mustards (for example, Mechlorethamine, cyclophosphamide,Cyclophosphamide Ifosfamide, Melphalan (L-sarcolysin), andChlorambucil), ethylenimines and methylmelamines (for example,Hexamethylmelamine and Thiotepa), alkyl sulfonates (for example,Busulfan), nitrosoureas (for example, Carmustine (BCNU), Lomustine(CCNU), Semustine (methyl-CCNU), and Streptozocin (streptozotocin)),triazenes (for example, Dacarbazine (DTIC;dimethyltriazenoimidazolecarboxamide)), folic acid analogs (for example,Methotrexate (amethopterin)), pyrimidine analogs (for example,Fluorouacil (5-fluorouracil; 5-FU), Floxuridine (fluorodeoxyuridine;FudR), and Cytarabine (cytosine arabinoside)), purine analogs andrelated inhibitors (for example, Mercaptopurine (6-mercaptopurine;6-MP), Thioguanine (6-thioguanine; TG), and Pentostatin(2′-deoxycoformycin)), vinca alkaloids (for example, Vinblastine (VLB,vinblastine sulfate)) and Vincristine (vincristine sulfate)),epipodophyllotoxins (for example, Etoposide and Teniposide), antibiotics(for example, Dactinomycin (actinomycin D), Daunorubicin (daunomycin;rubidomycin), Doxorubicin, Bleomycin, Plicamycin (mithramycin), andMitomycin (mitomycin C), enzymes (for example, L-Asparaginase),biological response modifiers (for example, Interferon-alpha andinterferon-alpha-2b), platinum coordination compounds (for example,Cisplatin (cis-DDP) and Carboplatin), anthracenedione (Mitoxantrone),substituted ureas (for example, Hydroxyurea), methylhydrazinederivatives (for example, Procarbazine (N-methylhydrazine; MIH),adrenocorticosteroids (for example, Prednisone), progestins (forexample, Hydroxyprogesterone caproate, Medroxyprogesterone,Medroxyprogesterone acetate, and Megestrol acetate), estrogens (forexample, Diethylstilbestrol (DES), Diethylstilbestrol diphosphate,Estradiol, and Ethinyl estradiol), antiestrogens (for example,Tamoxifen), androgens (Testosterone proprionate, and Fluoxymesterone),antiandrogens (for example, Flutamide), gonadotropin-releasing horomoneanalogs (for example, Leuprolide), other hormones and hormone analogs(for example, methyltestosterone, estramustine, estramustine phosphatesodium, chlorotrianisene, and testolactone), and others (for example,dicarbazine, glutamic acid, and mitotane).

In one embodiment, the compositions of the invention are administered incombination with one or more of the following drugs: infliximab (alsoknown as Remicade™ Centocor, Inc.), Trocade (Roche, RO-32-3555),Leflunomide (also known as Arava™ from Hoechst Marion Roussel), Kineret™(an IL-1 Receptor antagonist also known as Anakinra from Amgen, Inc.)

In a specific embodiment, compositions of the invention are administeredin combination with CHOP (cyclophosphamide, doxorubicin, vincristine,and prednisone) or combination of one or more of the components of CHOP.In one embodiment, the compositions of the invention are administered incombination with anti-CD20 antibodies, human monoclonal anti-CD20antibodies. In another embodiment, the compositions of the invention areadministered in combination with anti-CD20 antibodies and CHOP, oranti-CD20 antibodies and any combination of one or more of thecomponents of CHOP, particularly cyclophosphamide and/or prednisone. Ina specific embodiment, compositions of the invention are administered incombination with Rituximab. In a further embodiment, compositions of theinvention are administered with Rituximab and CHOP, or Rituximab and anycombination of one or more of the components of CHOP, particularlycyclophosphamide and/or prednisone. In a specific embodiment,compositions of the invention are administered in combination withtositumomab. In a further embodiment, compositions of the invention areadministered with tositumomab and CHOP, or tositumomab and anycombination of one or more of the components of CHOP, particularlycyclophosphamide and/or prednisone. The anti-CD20 antibodies mayoptionally be associated with radioisotopes, toxins or cytotoxicprodrugs.

In another specific embodiment, the compositions of the invention areadministered in combination Zevalin™. In a further embodiment,compositions of the invention are administered with Zevalin™ and CHOP,or Zevalin™ and any combination of one or more of the components ofCHOP, particularly cyclophosphamide and/or prednisone. Zevalin™ may beassociated with one or more radisotopes. Particularly preferred isotopesare ⁹⁰Y and ¹¹¹In.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with cytokines. Cytokines that may beadministered with the Therapeutics of the invention include, but are notlimited to, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15,anti-CD40, CD40L, IFN-gamma and TNF-alpha. In another embodiment,Therapeutics of the invention may be administered with any interleukin,including, but not limited to, IL-1alpha, IL-1beta, IL-2, IL-3, IL-4,IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1, IL-12, IL-13, IL-14, IL-15,IL-16, IL-17, IL-18, IL-19, IL-20, and IL-21.

In one embodiment, the Therapeutics of the invention are administered incombination with members of the TNF family. TNF, TNF-related or TNF-likemolecules that may be administered with the Therapeutics of theinvention include, but are not limited to, soluble forms of TNF-alpha,lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found incomplex heterotrimer LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L,4-1BBL, DcR3, OX40L, TNF-gamma (International Publication No. WO96/14328), AIM-I (International Publication No. WO 97/33899),endokine-alpha (International Publication No. WO 98/07880), OPG, andneutrokine-alpha (International Publication No. WO 98/18921, OX40, andnerve growth factor (NGF), and soluble forms of Fas, CD30, CD27, CD40and 4-IBB, TR2 (International Publication No. WO 96/34095), DR3(International Publication No. WO 97/33904), DR4 (InternationalPublication No. WO 98/32856), TR5 (International Publication No. WO98/30693), TRANK, TR9 (International Publication No. WO 98/56892), TR10(International Publication No. WO 98/54202), 312C2 (InternationalPublication No. WO 98/06842), and TR12, and soluble forms CD154, CD70,and CD153.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with angiogenic proteins. Angiogenicproteins that may be administered with the Therapeutics of the inventioninclude, but are not limited to, Glioma Derived Growth Factor (GDGF), asdisclosed in European Patent Number EP-399816; Platelet Derived GrowthFactor-A (PDGF-A), as disclosed in European Patent Number EP-682110;Platelet Derived Growth Factor-B (PDGF-B), as disclosed in EuropeanPatent Number EP-282317; Placental Growth Factor (PlGF), as disclosed inInternational Publication Number WO 92/06194; Placental Growth Factor-2(PlGF-2), as disclosed in Hauser et al., Growth Factors, 4:259-268(1993); Vascular Endothelial Growth Factor (VEGF), as disclosed inInternational Publication Number WO 90/13649; Vascular EndothelialGrowth Factor-A (VEGF-A), as disclosed in European Patent NumberEP-506477; Vascular Endothelial Growth Factor-2 (VEGF-2), as disclosedin International Publication Number WO 96/39515; Vascular EndothelialGrowth Factor B (VEGF-3); Vascular Endothelial Growth Factor B-186(VEGF-B186), as disclosed in International Publication Number WO96/26736; Vascular Endothelial Growth Factor-D (VEGF-D), as disclosed inInternational Publication Number WO 98/02543; Vascular EndothelialGrowth Factor-D (VEGF-D), as disclosed in International PublicationNumber WO 98/07832; and Vascular Endothelial Growth Factor-E (VEGF-E),as disclosed in German Patent Number DE19639601. The above mentionedreferences are herein incorporated by reference in their entireties.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with Fibroblast Growth Factors. FibroblastGrowth Factors that may be administered with the Therapeutics of theinvention include, but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4,FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13,FGF-14, and FGF-15.

In an additional embodiment, the Therapeutics of the invention areadministered in combination with hematopoietic growth factors.Hematopoietic growth factors that may be administered with theTherapeutics of the invention include, but are not limited to,granulocyte macrophage colony stimulating factor (GM-CSF) (sargramostim,LEUKINE™, PROKINE™), granulocyte colony stimulating factor (G-CSF)(filgrastim, NEUPOGEN™), macrophage colony stimulating factor (M-CSF,CSF-1) erythropoietin (epoetin alfa, EPOGEN™, PROCRIT™), stem cellfactor (SCF, c-kit ligand, steel factor), megakaryocyte colonystimulating factor, PIXY321 (a GMCSF/IL-3 fusion protein), interleukins,especially any one or more of IL-1 through IL-12, interferon-gamma, orthrombopoietin.

In certain embodiments, Therapeutics of the present invention areadministered in combination with adrenergic blockers, such as, forexample, acebutolol, atenolol, betaxolol, bisoprolol, carteolol,labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol,propranolol, sotalol, and timolol.

In another embodiment, the Therapeutics of the invention areadministered in combination with an antiarrhythmic drug (e.g.,adenosine, amidoarone, bretylium, digitalis, digoxin, digitoxin,diliazem, disopyramide, esmolol, flecainide, lidocaine, mexiletine,moricizine, phenyloin, procainamide, N-acetyl procainamide, propafenone,propranolol, quinidine, sotalol, tocainide, and verapamil).

In another embodiment, the Therapeutics of the invention areadministered in combination with diuretic agents, such as carbonicanhydrase-inhibiting agents (e.g., acetazolamide, dichlorphenamide, andmethazolamide), osmotic diuretics (e.g., glycerin, isosorbide, mannitol,and urea), diuretics that inhibit Na⁺—K⁺-2Cl⁻ symport (e.g., furosemide,bumetanide, azosemide, piretanide, tripamide, ethacrynic acid,muzolimine, and torsemide), thiazide and thiazide-like diuretics (e.g.,bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichormethiazide,chlorthalidone, indapamide, metolazone, and quinethazone), potassiumsparing diuretics (e.g., amiloride and triamterene), andmineralcorticoid receptor antagonists (e.g., spironolactone, canrenone,and potassium canrenoate).

In one embodiment, the Therapeutics of the invention are administered incombination with treatments for endocrine and/or hormone imbalancedisorders. Treatments for endocrine and/or hormone imbalance disordersinclude, but are not limited to, ¹²⁷I, radioactive isotopes of iodinesuch as ¹³¹I and ¹²³¹I; recombinant growth hormone, such as HUMATROPE™(recombinant somatropin); growth hormone analogs such as PROTROPIN™(somatrem); dopamine agonists such as PARLODEL™ (bromocriptine);somatostatin analogs such as SANDOSTATIN™ (octreotide); gonadotropinpreparations such as PREGNYL™, A.P.L.™ and PROFASI™ (chorionicgonadotropin (CG)), PERGONAL™ (menotropins), and METRODIN™(urofollitropin (uFSH)); synthetic human gonadotropin releasing hormonepreparations such as FACTREL™ and LUTREPULSE™ (gonadorelinhydrochloride); synthetic gonadotropin agonists such as LUPRON™(leuprolide acetate), SUPPRELIN™ (histrelin acetate), SYNAREL™(nafarelin acetate), and ZOLADEX™ (goserelin acetate); syntheticpreparations of thyrotropin-releasing hormone such as RELEFACT TRH™ andTHYPINONE™ (protirelin); recombinant human TSH such as THYROGEN™;synthetic preparations of the sodium salts of the natural isomers ofthyroid hormones such as L-T₄™, SYNTHROID™ and LEVOTHROID™(levothyroxine sodium), L-T₃™, CYTOMEL™ and TRIOSTAT™ (liothyroinesodium), and THYROLAR™ (liotrix); antithyroid compounds such as6-n-propylthiouracil (propylthiouracil), 1-methyl-2-mercaptoimidazoleand TAPAZOLE™ (methimazole), NEO-MERCAZOLE™ (carbimazole);beta-adrenergic receptor antagonists such as propranolol and esmolol;Ca²⁺ channel blockers; dexamethasone and iodinated radiological contrastagents such as TELEPAQUE™ (iopanoic acid) and ORAGRAFIN™ (sodiumipodate).

Additional treatments for endocrine and/or hormone imbalance disordersinclude, but are not limited to, estrogens or congugated estrogens suchas ESTRACE™ (estradiol), ESTINYL™ (ethinyl estradiol), PREMARIN™,ESTRATAB™, ORTHO-EST™, OGEN™ and estropipate (estrone), ESTROVIS™(quinestrol), ESTRADERM™ (estradiol), DELESTROGEN™ and VALERGEN™(estradiol valerate), DEPO-ESTRADIOL CYPIONATE™ and ESTROJECT LA™(estradiol cypionate); antiestrogens such as NOLVADEX™ (tamoxifen),SEROPHENE™ and CLOMID™ (clomiphene); progestins such as DURALUTIN™(hydroxyprogesterone caproate), MPA™ and DEPO-PROVERA™(medroxyprogesterone acetate), PROVERA™ and CYCRIN™ (MPA), MEGACE™(megestrol acetate), NORLUTIN™ (norethindrone), and NORLUTATE™ andAYGESTIN™ (norethindrone acetate); progesterone implants such asNORPLANT SYSTEM™ (subdermal implants of norgestrel); antiprogestins suchas RU 486™ (mifepristone); hormonal contraceptives such as ENOVID™(norethynodrel plus mestranol), PROGESTASERT™ (intrauterine device thatreleases progesterone), LOESTRIN™, BREVICON™, MODICON™, GENORA™,NELONA™, NORINYL™, OVACON-35™ and OVACON-50™ (ethinylestradiol/norethindrone), LEVLEN™, NORDETTE™, TRI-LEVLEN™ andTRIPHASIL-21™ (ethinyl estradiol/levonorgestrel) LO/OVRAL™ and OVRAL™(ethinyl estradiol/norgestrel), DEMULEN™ (ethinyl estradiol/ethynodioldiacetate), NORINYL™, ORTHO-NOVUM™, NORETHIN™, GENORA™, and NELOVA™(norethindrone/mestranol), DESOGEN™ and ORTHO-CEPT™ (ethinylestradiol/desogestrel), ORTHO-CYCLEN™ and ORTHO-TRICYCLEN™ (ethinylestradiol/norgestimate), MICRONOR™ and NOR-QD™ (norethindrone), andOVRETTE™ (norgestrel).

Additional treatments for endocrine and/or hormone imbalance disordersinclude, but are not limited to, testosterone esters such as methenoloneacetate and testosterone undecanoate; parenteral and oral androgens suchas TESTOJECT-50™ (testosterone), TESTEX™ (testosterone propionate),DELATESTRYL™ (testosterone enanthate), DEPO-TESTOSTERONE™ (testosteronecypionate), DANOCRINE™ (danazol), HALOTESTIN™ (fluoxymesterone), ORETONMETHYL™, TESTRED™ and VIRILON™ (methyltestosterone), and OXANDRIN™(oxandrolone); testosterone transdermal systems such as TESTODERM™;androgen receptor antagonist and 5-alpha-reductase inhibitors such asANDROCUR™ (cyproterone acetate), EULEXIN™ (flutamide), and PROSCAR™(finasteride); adrenocorticotropic hormone preparations such asCORTROSYN™ (cosyntropin); adrenocortical steroids and their syntheticanalogs such as ACLOVATE™ (alclometasone dipropionate), CYCLOCORT™(amcinonide), BECLOVENT™ and VANCERIL™ (beclomethasone dipropionate),CELESTONE™ (betamethasone), BENISONE™ and UTICORT™ (betamethasonebenzoate), DIPROSONE™ (betamethasone dipropionate), CELESTONE PHOSPHATE™(betamethasone sodium phosphate), CELESTONE SOLUSPAN™ (betamethasonesodium phosphate and acetate), BETA-VAL™ and VALISONE™ (betamethasonevalerate), TEMOVATE™ (clobetasol propionate), CLODERM™ (clocortolonepivalate), CORTEF™ and HYDROCORTONE™ (cortisol (hydrocortisone)),HYDROCORTONE ACETATE™ (cortisol (hydrocortisone) acetate), LOCOID™(cortisol (hydrocortisone) butyrate), HYDROCORTONE PHOSPHATE™ (cortisol(hydrocortisone) sodium phosphate), A-HYDROCORT™ and SOLU CORTEF™(cortisol (hydrocortisone) sodium succinate), WESTCORT™ (cortisol(hydrocortisone) valerate), CORTISONE ACETATE™ (cortisone acetate),DESOWEN™ and TRIDESILON™ (desonide), TOPICORT™ (desoximetasone),DECADRON™ (dexamethasone), DECADRON LA™ (dexamethasone acetate),DECADRON PHOSPHATE™ and HEXADROL PHOSPHATE™ (dexamethasone sodiumphosphate), FLORONE™ and MAXIFLOR™ (diflorasone diacetate), FLORINEFACETATE™ (fludrocortisone acetate), AEROBID™ and NASALIDE™(flunisolide), FLUONID™ and SYNALAR™ (fluocinolone acetonide), LIDEX™(fluocinonide), FLUOR-OP™ and FML™ (fluorometholone), CORDRAN™(flurandrenolide), HALOG™ (halcinonide), HMS LIZUIFILM™ (medrysone),MEDROL™ (methylprednisolone), DEPO-MEDROL™ and MEDROL ACETATE™(methylprednisone acetate), A-METHAPRED™ and SOLUMEDROL™(methylprednisolone sodium succinate), ELOCON™ (mometasone furoate),HALDRONE™ (paramethasone acetate), DELTA-CORTEF™ (prednisolone),ECONOPRED™ (prednisolone acetate), HYDELTRASOL™ (prednisolone sodiumphosphate), HYDELTRA-T.B.A™ (prednisolone tebutate), DELTASONE™(prednisone), ARISTOCORT™ and KENACORT™ (triamcinolone), KENALOG™(triamcinolone acetonide), ARISTOCORT™ and KENACORT DIACETATE™(triamcinolone diacetate), and ARISTOSPAN™ (triamcinolone hexacetonide);inhibitors of biosynthesis and action of adrenocortical steroids such asCYTADREN™ (aminoglutethimide), NIZORAL™ (ketoconazole), MODRASTANE™(trilostane), and METOPIRONE™ (metyrapone); bovine, porcine or humaninsulin or mixtures thereof; insulin analogs; recombinant human insulinsuch as HUMULIN™ and NOVOLIN™; oral hypoglycemic agents such as ORAMIDE™and ORINASE™ (tolbutamide), DIABINESE™ (chlorpropamide), TOLAMIDE™ andTOLINASE™ (tolazamide), DYMELOR™ (acetohexamide), glibenclamide,MICRONASE™, DIBETA™ and GLYNASE™ (glyburide), GLUCOTROL™ (glipizide),and DIAMICRON™ (gliclazide), GLUCOPHAGE™ (metformin), ciglitazone,pioglitazone, and alpha-glucosidase inhibitors; bovine or porcineglucagon; somatostatins such as SANDOSTATIN™ (octreotide); anddiazoxides such as PROGLYCEM™ (diazoxide).

In one embodiment, the Therapeutics of the invention are administered incombination with treatments for uterine motility disorders. Treatmentsfor uterine motility disorders include, but are not limited to, estrogendrugs such as conjugated estrogens (e.g., PREMARIN® and ESTRATAB®),estradiols (e.g., CLIMARA® and ALORA®), estropipate, andchlorotrianisene; progestin drugs (e.g., AMEN® (medroxyprogesterone),MICRONOR® (norethidrone acetate), PROMETRIUM® progesterone, andmegestrol acetate); and estrogen/progesterone combination therapies suchas, for example, conjugated estrogens/medroxyprogesterone (e.g.,PREMPRO™ and PREMPHASE®) and norethindrone acetate/ethinyl estsradiol(e.g., FEMHRT™).

In an additional embodiment, the Therapeutics of the invention areadministered in combination with drugs effective in treating irondeficiency and hypochromic anemias, including but not limited to,ferrous sulfate (iron sulfate, FEOSOL™), ferrous fumarate (e.g.,FEOSTAT™), ferrous gluconate (e.g., FERGON™), polysaccharide-ironcomplex (e.g., NIFEREX™), iron dextran injection (e.g., INFED™), cupricsulfate, pyroxidine, riboflavin, Vitamin B₁₂, cyancobalamin injection(e.g., REDISOL™, RUBRAMIN PC™), hydroxocobalamin, folic acid (e.g.,FOLVITE™), leucovorin (folinic acid, 5-CHOH4PteGlu, citrovorum factor)or WELLCOVORIN (Calcium salt of leucovorin), transferrin or ferritin.

In certain embodiments, the Therapeutics of the invention areadministered in combination with agents used to treat psychiatricdisorders. Psychiatric drugs that may be administered with theTherapeutics of the invention include, but are not limited to,antipsychotic agents (e.g., chlorpromazine, chlorprothixene, clozapine,fluphenazine, haloperidol, loxapine, mesoridazine, molindone,olanzapine, perphenazine, pimozide, quetiapine, risperidone,thioridazine, thiothixene, trifluoperazine, and triflupromazine),antimanic agents (e.g., carbamazepine, divalproex sodium, lithiumcarbonate, and lithium citrate), antidepressants (e.g., amitriptyline,amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin,fluvoxamine, fluoxetine, imipramine, isocarboxazid, maprotiline,mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine,protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, andvenlafaxine), antianxiety agents (e.g., alprazolam, buspirone,chlordiazepoxide, clorazepate, diazepam, halazepam, lorazepam, oxazepam,and prazepam), and stimulants (e.g., d-amphetamine, methylphenidate, andpemoline).

In other embodiments, the Therapeutics of the invention are administeredin combination with agents used to treat neurological disorders.Neurological agents that may be administered with the Therapeutics ofthe invention include, but are not limited to, antiepileptic agents(e.g., carbarnazepine, clonazepam, ethosuximide, phenobarbital,phenyloin, primidone, valproic acid, divalproex sodium, felbamate,gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine,topiramate, zonisamide, diazepam, lorazepam, and clonazepam),antiparkinsonian agents (e.g., levodopa/carbidopa, selegiline,amantidine, bromocriptine, pergolide, ropinirole, pramipexole,benztropine; biperiden; ethopropazine; procyclidine; trihexyphenidyl,tolcapone), and ALS therapeutics (e.g. riluzole).

In another embodiment, Therapeutics of the invention are administered incombination with vasodilating agents and/or calcium channel blockingagents. Vasodilating agents that may be administered with theTherapeutics of the invention include, but are not limited to,Angiotensin Converting Enzyme (ACE) inhibitors (e.g., papaverine,isoxsuprine, benazepril, captopril, cilazapril, enalapril, enalaprilat,fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril,spirapril, trandolapril, and nylidrin), and nitrates (e.g., isosorbidedinitrate, isosorbide mononitrate, and nitroglycerin). Examples ofcalcium channel blocking agents that may be administered in combinationwith the Therapeutics of the invention include, but are not limited toamlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine,nicardipine, nifedipine, nimodipine, and verapamil.

In certain embodiments, the Therapeutics of the invention areadministered in combination with treatments for gastrointestinaldisorders. Treatments for gastrointestinal disorders that may beadministered with the Therapeutic of the invention include, but are notlimited to, H₂ histamine receptor antagonists (e.g., TAGAMET™(cimetidine), ZANTAC™ (ranitidine), PEPCID™ (famotidine), and AXID™(nizatidine)); inhibitors of H⁺, K⁺ ATPase (e.g., PREVACID™(lansoprazole) and PRILOSEC™ (omeprazole)); Bismuth compounds (e.g.,PEPTO-BISMOL™ (bismuth subsalicylate) and DE-NOL™ (bismuth subcitrate));various antacids; sucralfate; prostaglandin analogs (e.g. CYTOTEC™(misoprostol)); muscarinic cholinergic antagonists; laxatives (e.g.,surfactant laxatives, stimulant laxatives, saline and osmoticlaxatives); antidiarrheal agents (e.g., LOMOTIL™ (diphenoxylate),MOTOFEN™ (diphenoxin), and IMODIUM™ (loperamide hydrochloride)),synthetic analogs of somatostatin such as SANDOSTATIN™ (octreotide),antiemetic agents (e.g., ZOFRAN™ (ondansetron), KYTRIL™ (granisetronhydrochloride), tropisetron, dolasetron, metoclopramide, chlorpromazine,perphenazine, prochlorperazine, promethazine, thiethylperazine,triflupromazine, domperidone, haloperidol, droperidol,trimethobenzamide, dexamethasone, methylprednisolone, dronabinol, andnabilone); D2 antagonists (e.g., metoclopramide, trimethobenzamide andchlorpromazine); bile salts; chenodeoxycholic acid; ursodeoxycholicacid; and pancreatic enzyme preparations such as pancreatin andpancrelipase.

In additional embodiments, the Therapeutics of the invention areadministered in combination with other therapeutic or prophylacticregimens, such as, for example, radiation therapy.

Example 14 Method of Treating Decreased Levels of the Polypeptide

The present invention relates to a method for treating an individual inneed of an increased level of a polypeptide of the invention in the bodycomprising administering to such an individual a composition comprisinga therapeutically effective amount of an agonist of the invention(including polypeptides of the invention). Moreover, it will beappreciated that conditions caused by a decrease in the standard ornormal expression level of a polypeptide of the present invention in anindividual can be treated by administering the agonist or antagonist ofthe present invention. Thus, the invention also provides a method oftreatment of an individual in need of an increased level of thepolypeptide comprising administering to such an individual a Therapeuticcomprising an amount of the agonist or antagonist to increase theactivity level of the polypeptide in such an individual.

For example, a patient with decreased levels of a polypeptide receives adaily dose 0.1-100 ug/kg of the agonist or antagonist for sixconsecutive days. The exact details of the dosing scheme, based onadministration and formulation, are provided in Example 13.

Example 15 Method of Treating Increased Levels of the Polypeptide

The present invention also relates to a method of treating an individualin need of a decreased level of a polypeptide of the invention in thebody comprising administering to such an individual a compositioncomprising a therapeutically effective amount of an antagonist of theinvention (including polypeptides and antibodies of the invention).

In one example, antisense technology is used to inhibit production of apolypeptide of the present invention. This technology is one example ofa method of decreasing levels of a polypeptide, due to a variety ofetiologies, such as cancer.

For example, a patient diagnosed with abnormally increased levels of apolypeptide is administered intravenously antisense polynucleotides at0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment isrepeated after a 7-day rest period if the treatment was well tolerated.The antisense polynucleotides of the present invention can be formulatedusing techniques and formulations described herein (e.g. see Example13), or otherwise known in the art.

Example 16 Method of Treatment Using Gene Therapy-Ex Vivo

One method of gene therapy transplants fibroblasts, which are capable ofexpressing a polypeptide, onto a patient. Generally, fibroblasts areobtained from a subject by skin biopsy. The resulting tissue is placedin tissue-culture medium and separated into small pieces. Small chunksof the tissue are placed on a wet surface of a tissue culture flask,approximately ten pieces are placed in each flask. The flask is turnedupside down, closed tight and left at room temperature over night. After24 hours at room temperature, the flask is inverted and the chunks oftissue remain fixed to the bottom of the flask and fresh media (e.g.,Ham's F12 media, with 10% FBS, penicillin and streptomycin) is added.The flasks are then incubated at 37 degree C. for approximately oneweek.

At this time, fresh media is added and subsequently changed everyseveral days. After an additional two weeks in culture, a monolayer offibroblasts emerge. The monolayer is trypsinized and scaled into largerflasks.

pMV-7 (Kirschmeier, P. T. et al., DNA, 7:219-25 (1988)), flanked by thelong terminal repeats of the Moloney murine sarcoma virus, is digestedwith EcoRI and HindIII and subsequently treated with calf intestinalphosphatase. The linear vector is fractionated on agarose gel andpurified, using glass beads.

The cDNA encoding a polypeptide of the present invention can beamplified using PCR primers which correspond to the 5′ and 3′ endsequences respectively as set forth in Example 1 using primers andhaving appropriate restriction sites and initiation/stop codons, ifnecessary. Preferably, the 5′ primer contains an EcoRI site and the 3′primer includes a HindIII site. Equal quantities of the Moloney murinesarcoma virus linear backbone and the amplified EcoRI and HindIIIfragment are added together, in the presence of T4 DNA ligase. Theresulting mixture is maintained under conditions appropriate forligation of the two fragments. The ligation mixture is then used totransform bacteria HB101, which are then plated onto agar containingkanamycin for the purpose of confirming that the vector has the gene ofinterest properly inserted.

The amphotropic pA317 or GP+am12 packaging cells are grown in tissueculture to confluent density in Dulbecco's Modified Eagles Medium (DMEM)with 10% calf serum (CS), penicillin and streptomycin. The MSV vectorcontaining the gene is then added to the media and the packaging cellstransduced with the vector. The packaging cells now produce infectiousviral particles containing the gene (the packaging cells are nowreferred to as producer cells).

Fresh media is added to the transduced producer cells, and subsequently,the media is harvested from a 10 cm plate of confluent producer cells.The spent media, containing the infectious viral particles, is filteredthrough a millipore filter to remove detached producer cells and thismedia is then used to infect fibroblast cells. Media is removed from asub-confluent plate of fibroblasts and quickly replaced with the mediafrom the producer cells. This media is removed and replaced with freshmedia. If the titer of virus is high, then virtually all fibroblastswill be infected and no selection is required. If the titer is very low,then it is necessary to use a retroviral vector that has a selectablemarker, such as neo or his. Once the fibroblasts have been efficientlyinfected, the fibroblasts are analyzed to determine whether protein isproduced.

The engineered fibroblasts are then transplanted onto the host, eitheralone or after having been grown to confluence on cytodex 3 microcarrierbeads.

Example 17 Gene Therapy Using Endogenous Genes Corresponding ToPolynucleotides of the Invention

Another method of gene therapy according to the present inventioninvolves operably associating the endogenous polynucleotide sequence ofthe invention with a promoter via homologous recombination as described,for example, in U.S. Pat. No. 5,641,670, issued Jun. 24, 1997;International Publication NO: WO 96/29411, published Sep. 26, 1996;International Publication NO: WO 94/12650, published Aug. 4, 1994;Koller et al., Proc. Natl. Acad. Sci. USA, 86:8932-8935 (1989); andZijlstra et al., Nature, 342:435-438 (1989). This method involves theactivation of a gene which is present in the target cells, but which isnot expressed in the cells, or is expressed at a lower level thandesired.

Polynucleotide constructs are made which contain a promoter andtargeting sequences, which are homologous to the 5′ non-coding sequenceof endogenous polynucleotide sequence, flanking the promoter. Thetargeting sequence will be sufficiently near the 5′ end of thepolynucleotide sequence so the promoter will be operably linked to theendogenous sequence upon homologous recombination. The promoter and thetargeting sequences can be amplified using PCR. Preferably, theamplified promoter contains distinct restriction enzyme sites on the 5′and 3′ ends. Preferably, the 3′ end of the first targeting sequencecontains the same restriction enzyme site as the 5′ end of the amplifiedpromoter and the 5′ end of the second targeting sequence contains thesame restriction site as the 3′ end of the amplified promoter.

The amplified promoter and the amplified targeting sequences aredigested with the appropriate restriction enzymes and subsequentlytreated with calf intestinal phosphatase. The digested promoter anddigested targeting sequences are added together in the presence of T4DNA ligase. The resulting mixture is maintained under conditionsappropriate for ligation of the two fragments. The construct is sizefractionated on an agarose gel, then purified by phenol extraction andethanol precipitation.

In this Example, the polynucleotide constructs are administered as nakedpolynucleotides via electroporation. However, the polynucleotideconstructs may also be administered with transfection-facilitatingagents, such as liposomes, viral sequences, viral particles,precipitating agents, etc. Such methods of delivery are known in theart.

Once the cells are transfected, homologous recombination will take placewhich results in the promoter being operably linked to the endogenouspolynucleotide sequence. This results in the expression ofpolynucleotide corresponding to the polynucleotide in the cell.Expression may be detected by immunological staining, or any othermethod known in the art.

Fibroblasts are obtained from a subject by skin biopsy. The resultingtissue is placed in DMEM+10% fetal calf serum. Exponentially growing orearly stationary phase fibroblasts are trypsinized and rinsed from theplastic surface with nutrient medium. An aliquot of the cell suspensionis removed for counting, and the remaining cells are subjected tocentrifugation. The supernatant is aspirated and the pellet isresuspended in 5 ml of electroporation buffer (20 mM HEPES pH 7.3, 137mM NaCl, 5 mM KCl, 0.7 mM Na₂ HPO₄, 6 mM dextrose). The cells arerecentrifuged, the supernatant aspirated, and the cells resuspended inelectroporation buffer containing 1 mg/ml acetylated bovine serumalbumin. The final cell suspension contains approximately 3×10⁶cells/ml. Electroporation should be performed immediately followingresuspension.

Plasmid DNA is prepared according to standard techniques. For example,to construct a plasmid for targeting to the locus corresponding to thepolynucleotide of the invention, plasmid pUC18 (MBI Fermentas, Amherst,N.Y.) is digested with HindIII. The CMV promoter is amplified by PCRwith an XbaI site on the 5′ end and a BamHI site on the 3′ end. Twonon-coding sequences are amplified via PCR: one non-coding sequence(fragment 1) is amplified with a HindIII site at the 5′ end and an Xbasite at the 3′ end; the other non-coding sequence (fragment 2) isamplified with a BamHI site at the 5′end and a HindIII site at the 3′end. The CMV promoter and the fragments (1 and 2) are digested with theappropriate enzymes (CMV promoter—XbaI and BamHI; fragment 1—XbaI;fragment 2—BamHI) and ligated together. The resulting ligation productis digested with HindIII, and ligated with the HindIII-digested pUC18plasmid.

Plasmid DNA is added to a sterile cuvette with a 0.4 cm electrode gap(Bio-Rad). The final DNA concentration is generally at least 120 μg/ml.0.5 ml of the cell suspension (containing approximately 1.5×10⁶ cells)is then added to the cuvette, and the cell suspension and DNA solutionsare gently mixed. Electroporation is performed with a Gene-Pulserapparatus (Bio-Rad). Capacitance and voltage are set at 960 μF and250-300 V, respectively. As voltage increases, cell survival decreases,but the percentage of surviving cells that stably incorporate theintroduced DNA into their genome increases dramatically. Given theseparameters, a pulse time of approximately 14-20 mSec should be observed.

Electroporated cells are maintained at room temperature forapproximately 5 min, and the contents of the cuvette are then gentlyremoved with a sterile transfer pipette. The cells are added directly to10 ml of prewarmed nutrient media (DMEM with 15% calf serum) in a 10 cmdish and incubated at 37 degree C. The following day, the media isaspirated and replaced with 10 ml of fresh media and incubated for afurther 16-24 hours.

The engineered fibroblasts are then injected into the host, either aloneor after having been grown to confluence on cytodex 3 microcarrierbeads. The fibroblasts now produce the protein product. The fibroblastscan then be introduced into a patient as described above.

Example 18 Method of Treatment Using Gene Therapy—In Vivo

Another aspect of the present invention is using in vivo gene therapymethods to treat disorders, diseases and conditions. The gene therapymethod relates to the introduction of naked nucleic acid (DNA, RNA, andantisense DNA or RNA) sequences into an animal to increase or decreasethe expression of the polypeptide. The polynucleotide of the presentinvention may be operatively linked to (i.e., associated with) apromoter or any other genetic elements necessary for the expression ofthe polypeptide by the target tissue. Such gene therapy and deliverytechniques and methods are known in the art, see, for example,WO90/11092, WO98/11779; U.S. Pat. Nos. 5,693,622, 5,705,151, 5,580,859;Tabata et al., Cardiovasc. Res. 35(3):470-479 (1997); Chao et al.,Pharmacol. Res. 35(6):517-522 (1997); Wolff, Neuromuscul. Disord.7(5):314-318 (1997); Schwartz et al., Gene Ther. 3(5):405-411 (1996);Tsurumi et al., Circulation 94(12):3281-3290 (1996) (incorporated hereinby reference).

The polynucleotide constructs may be delivered by any method thatdelivers injectable materials to the cells of an animal, such as,injection into the interstitial space of tissues (heart, muscle, skin,lung, liver, intestine and the like). The polynucleotide constructs canbe delivered in a pharmaceutically acceptable liquid or aqueous carrier.

The term “naked” polynucleotide, DNA or RNA, refers to sequences thatare free from any delivery vehicle that acts to assist, promote, orfacilitate entry into the cell, including viral sequences, viralparticles, liposome formulations, lipofectin or precipitating agents andthe like. However, the polynucleotides of the present invention may alsobe delivered in liposome formulations (such as those taught in FelgnerP. L. et al. (1995) Ann. NY Acad. Sci. 772:126-139 and Abdallah B. etal. (1995) Biol. Cell 85(1):1-7) which can be prepared by methods wellknown to those skilled in the art.

The polynucleotide vector constructs used in the gene therapy method arepreferably constructs that will not integrate into the host genome norwill they contain sequences that allow for replication. Any strongpromoter known to those skilled in the art can be used for driving theexpression of DNA. Unlike other gene therapy techniques, one majoradvantage of introducing naked nucleic acid sequences into target cellsis the transitory nature of the polynucleotide synthesis in the cells.Studies have shown that non-replicating DNA sequences can be introducedinto cells to provide production of the desired polypeptide for periodsof up to six months.

The polynucleotide construct can be delivered to the interstitial spaceof tissues within an animal, including muscle, skin, brain, lung, liver,spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage,pancreas, kidney, gall bladder, stomach, intestine, testis, ovary,uterus, rectum, nervous system, eye, gland, and connective tissue.Interstitial space of the tissues comprises the intercellular fluid,mucopolysaccharide matrix among the reticular fibers of organ tissues,elastic fibers in the walls of vessels or chambers, collagen fibers offibrous tissues, or that same matrix within connective tissueensheathing muscle cells or in the lacunae of bone. It is similarly thespace occupied by the plasma of the circulation and the lymph fluid ofthe lymphatic channels. Delivery to the interstitial space of muscletissue is preferred for the reasons discussed below. They may beconveniently delivered by injection into the tissues comprising thesecells. They are preferably delivered to and expressed in persistent,non-dividing cells which are differentiated, although delivery andexpression may be achieved in non-differentiated or less completelydifferentiated cells, such as, for example, stem cells of blood or skinfibroblasts. In vivo muscle cells are particularly competent in theirability to take up and express polynucleotides.

For the naked polynucleotide injection, an effective dosage amount ofDNA or RNA will be in the range of from about 0.05 g/kg body weight toabout 50 mg/kg body weight. Preferably the dosage will be from about0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kgto about 5 mg/kg. Of course, as the artisan of ordinary skill willappreciate, this dosage will vary according to the tissue site ofinjection. The appropriate and effective dosage of nucleic acid sequencecan readily be determined by those of ordinary skill in the art and maydepend on the condition being treated and the route of administration.The preferred route of administration is by the parenteral route ofinjection into the interstitial space of tissues. However, otherparenteral routes may also be used, such as, inhalation of an aerosolformulation particularly for delivery to lungs or bronchial tissues,throat or mucous membranes of the nose. In addition, nakedpolynucleotide constructs can be delivered to arteries duringangioplasty by the catheter used in the procedure.

The dose response effects of injected polynucleotide in muscle in vivois determined as follows. Suitable template DNA for production of mRNAcoding for polypeptide of the present invention is prepared inaccordance with a standard recombinant DNA methodology. The templateDNA, which may be either circular or linear, is either used as naked DNAor complexed with liposomes. The quadriceps muscles of mice are theninjected with various amounts of the template DNA.

Five to six week old female and male Balb/C mice are anesthetized byintraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incisionis made on the anterior thigh, and the quadriceps muscle is directlyvisualized. The template DNA is injected in 0.1 ml of carrier in a 1 ccsyringe through a 27 gauge needle over one minute, approximately 0.5 cmfrom the distal insertion site of the muscle into the knee and about 0.2cm deep. A suture is placed over the injection site for futurelocalization, and the skin is closed with stainless steel clips.

After an appropriate incubation time (e.g., 7 days) muscle extracts areprepared by excising the entire quadriceps. Every fifth 15 umcross-section of the individual quadriceps muscles is histochemicallystained for protein expression. A time course for protein expression maybe done in a similar fashion except that quadriceps from different miceare harvested at different times. Persistence of DNA in muscle followinginjection may be determined by Southern blot analysis after preparingtotal cellular DNA and HIRT supernatants from injected and control mice.The results of the above experimentation in mice can be used toextrapolate proper dosages and other treatment parameters in humans andother animals using naked DNA.

Example 19 Transgenic Animals

The polypeptides of the invention can also be expressed in transgenicanimals. Animals of any species, including, but not limited to, mice,rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep,cows and non-human primates, e.g., baboons, monkeys, and chimpanzees maybe used to generate transgenic animals. In a specific embodiment,techniques described herein or otherwise known in the art, are used toexpress polypeptides of the invention in humans, as part of a genetherapy protocol.

Any technique known in the art may be used to introduce the transgene(i.e., polynucleotides of the invention) into animals to produce thefounder lines of transgenic animals. Such techniques include, but arenot limited to, pronuclear microinjection (Paterson et al., Appl.Microbiol. Biotechnol. 40:691-698 (1994); Carver et al., Biotechnology(NY) 11:1263-1270 (1993); Wright et al., Biotechnology (NY) 9:830-834(1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirusmediated gene transfer into germ lines (Van der Putten et al., Proc.Natl. Acad. Sci., USA 82:6148-6152 (1985)), blastocysts or embryos; genetargeting in embryonic stem cells (Thompson et al., Cell 56:313-321(1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol.3:1803-1814 (1983)); introduction of the polynucleotides of theinvention using a gene gun (see, e.g., Ulmer et al., Science 259:1745(1993); introducing nucleic acid constructs into embryonic pleuripotentstem cells and transferring the stem cells back into the blastocyst; andsperm-mediated gene transfer (Lavitrano et al., Cell 57:717-723 (1989);etc. For a review of such techniques, see Gordon, “Transgenic Animals,”Intl. Rev. Cytol. 115:171-229 (1989), which is incorporated by referenceherein in its entirety.

Any technique known in the art may be used to produce transgenic clonescontaining polynucleotides of the invention, for example, nucleartransfer into enucleated oocytes of nuclei from cultured embryonic,fetal, or adult cells induced to quiescence (Campell et al., Nature380:64-66 (1996); Wilmut et al., Nature 385:810-813 (1997)).

The present invention provides for transgenic animals that carry thetransgene in all their cells, as well as animals which carry thetransgene in some, but not all their cells, i.e., mosaic animals orchimeric. The transgene may be integrated as a single transgene or asmultiple copies such as in concatamers, e.g., head-to-head tandems orhead-to-tail tandems. The transgene may also be selectively introducedinto and activated in a particular cell type by following, for example,the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA89:6232-6236 (1992)). The regulatory sequences required for such acell-type specific activation will depend upon the particular cell typeof interest, and will be apparent to those of skill in the art. When itis desired that the polynucleotide transgene be integrated into thechromosomal site of the endogenous gene, gene targeting is preferred.Briefly, when such a technique is to be utilized, vectors containingsome nucleotide sequences homologous to the endogenous gene are designedfor the purpose of integrating, via homologous recombination withchromosomal sequences, into and disrupting the function of thenucleotide sequence of the endogenous gene. The transgene may also beselectively introduced into a particular cell type, thus inactivatingthe endogenous gene in only that cell type, by following, for example,the teaching of Gu et al. (Gu et al., Science 265:103-106 (1994)). Theregulatory sequences required for such a cell-type specific inactivationwill depend upon the particular cell type of interest, and will beapparent to those of skill in the art.

Once transgenic animals have been generated, the expression of therecombinant gene may be assayed utilizing standard techniques. Initialscreening may be accomplished by Southern blot analysis or PCRtechniques to analyze animal tissues to verify that integration of thetransgene has taken place. The level of mRNA expression of the transgenein the tissues of the transgenic animals may also be assessed usingtechniques which include, but are not limited to, Northern blot analysisof tissue samples obtained from the animal, in situ hybridizationanalysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenicgene-expressing tissue may also be evaluated immunocytochemically orimmunohistochemically using antibodies specific for the transgeneproduct.

Once the founder animals are produced, they may be bred, inbred,outbred, or crossbred to produce colonies of the particular animal.Examples of such breeding strategies include, but are not limited to:outbreeding of founder animals with more than one integration site inorder to establish separate lines; inbreeding of separate lines in orderto produce compound transgenics that express the transgene at higherlevels because of the effects of additive expression of each transgene;crossing of heterozygous transgenic animals to produce animalshomozygous for a given integration site in order to both augmentexpression and eliminate the need for screening of animals by DNAanalysis; crossing of separate homozygous lines to produce compoundheterozygous or homozygous lines; and breeding to place the transgene ona distinct background that is appropriate for an experimental model ofinterest.

Transgenic animals of the invention have uses which include, but are notlimited to, animal model systems useful in elaborating the biologicalfunction of polypeptides of the present invention, studying conditionsand/or disorders associated with aberrant expression, and in screeningfor compounds effective in ameliorating such conditions and/ordisorders.

Example 20 Knock-Out Animals

Endogenous gene expression can also be reduced by inactivating or“knocking out” the gene and/or its promoter using targeted homologousrecombination. (e.g., see Smithies et al., Nature 317:230-234 (1985);Thomas & Capecchi, Cell 51:503-512 (1987); Thompson et al., Cell5:313-321 (1989); each of which is incorporated by reference herein inits entirety). For example, a mutant, non-functional polynucleotide ofthe invention (or a completely unrelated DNA sequence) flanked by DNAhomologous to the endogenous polynucleotide sequence (either the codingregions or regulatory regions of the gene) can be used, with or withouta selectable marker and/or a negative selectable marker, to transfectcells that express polypeptides of the invention in vivo. In anotherembodiment, techniques known in the art are used to generate knockoutsin cells that contain, but do not express the gene of interest.Insertion of the DNA construct, via targeted homologous recombination,results in inactivation of the targeted gene. Such approaches areparticularly suited in research and agricultural fields wheremodifications to embryonic stem cells can be used to generate animaloffspring with an inactive targeted gene (e.g., see Thomas & Capecchi1987 and Thompson 1989, supra). However this approach can be routinelyadapted for use in humans provided the recombinant DNA constructs aredirectly administered or targeted to the required site in vivo usingappropriate viral vectors that will be apparent to those of skill in theart.

In further embodiments of the invention, cells that are geneticallyengineered to express the polypeptides of the invention, oralternatively, that are genetically engineered not to express thepolypeptides of the invention (e.g., knockouts) are administered to apatient in vivo. Such cells may be obtained from the patient (i.e.,animal, including human) or an MHC compatible donor and can include, butare not limited to fibroblasts, bone marrow cells, blood cells (e.g.,lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cellsare genetically engineered in vitro using recombinant DNA techniques tointroduce the coding sequence of polypeptides of the invention into thecells, or alternatively, to disrupt the coding sequence and/orendogenous regulatory sequence associated with the polypeptides of theinvention, e.g., by transduction (using viral vectors, and preferablyvectors that integrate the transgene into the cell genome) ortransfection procedures, including, but not limited to, the use ofplasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc. Thecoding sequence of the polypeptides of the invention can be placed underthe control of a strong constitutive or inducible promoter orpromoter/enhancer to achieve expression, and preferably secretion, ofthe polypeptides of the invention. The engineered cells which expressand preferably secrete the polypeptides of the invention can beintroduced into the patient systemically, e.g., in the circulation, orintraperitoneally.

Alternatively, the cells can be incorporated into a matrix and implantedin the body, e.g., genetically engineered fibroblasts can be implantedas part of a skin graft; genetically engineered endothelial cells can beimplanted as part of a lymphatic or vascular graft. (See, for example,Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan & Wilson, U.S.Pat. No. 5,460,959 each of which is incorporated by reference herein inits entirety).

When the cells to be administered are non-autologous or non-MHCcompatible cells, they can be administered using well known techniqueswhich prevent the development of a host immune response against theintroduced cells. For example, the cells may be introduced in anencapsulated form which, while allowing for an exchange of componentswith the immediate extracellular environment, does not allow theintroduced cells to be recognized by the host immune system.

Transgenic and “knock-out” animals of the invention have uses whichinclude, but are not limited to, animal model systems useful inelaborating the biological function of polypeptides of the presentinvention, studying conditions and/or disorders associated with aberrantexpression, and in screening for compounds effective in amelioratingsuch conditions and/or disorders.

Example 21 Assays Detecting Stimulation or Inhibition of B cellProliferation and Differentiation

Generation of functional humoral immune responses requires both solubleand cognate signaling between B-lineage cells and theirmicroenvironment. Signals may impart a positive stimulus that allows aB-lineage cell to continue its programmed development, or a negativestimulus that instructs the cell to arrest its current developmentalpathway. To date, numerous stimulatory and inhibitory signals have beenfound to influence B cell responsiveness including IL-2, IL-4, IL-5,IL-6, IL-7, IL10, IL-13, IL-14 and IL-15. Interestingly, these signalsare by themselves weak effectors but can, in combination with variousco-stimulatory proteins, induce activation, proliferation,differentiation, homing, tolerance and death among B cell populations.

One of the best studied classes of B-cell co-stimulatory proteins is theTNF-superfamily. Within this family CD40, CD27, and CD30 along withtheir respective ligands CD154, CD70, and CD153 have been found toregulate a variety of immune responses. Assays which allow for thedetection and/or observation of the proliferation and differentiation ofthese B-cell populations and their precursors are valuable tools indetermining the effects various proteins may have on these B-cellpopulations in terms of proliferation and differentiation. Listed beloware two assays designed to allow for the detection of thedifferentiation, proliferation, or inhibition of B-cell populations andtheir precursors.

In Vitro Assay—Agonists or antagonists of the invention can be assessedfor its ability to induce activation, proliferation, differentiation orinhibition and/or death in B-cell populations and their precursors. Theactivity of the agonists or antagonists of the invention on purifiedhuman tonsillar B cells, measured qualitatively over the dose range from0.1 to 10,000 ng/mL, is assessed in a standard B-lymphocyteco-stimulation assay in which purified tonsillar B cells are cultured inthe presence of either formalin-fixed Staphylococcus aureus Cowan I(SAC) or immobilized anti-human IgM antibody as the priming agent.Second signals such as IL-2 and IL-15 synergize with SAC and IgMcrosslinking to elicit B cell proliferation as measured bytritiated-thymidine incorporation. Novel synergizing agents can bereadily identified using this assay. The assay involves isolating humantonsillar B cells by magnetic bead (MACS) depletion of CD3-positivecells. The resulting cell population is greater than 95% B cells asassessed by expression of CD45R(B220).

Various dilutions of each sample are placed into individual wells of a96-well plate to which are added 10⁵ B-cells suspended in culture medium(RPMI 1640 containing 10% FBS, 5×10⁻⁵M 2ME, 100 U/ml penicillin, 10ug/ml streptomycin, and 10⁻⁵ dilution of SAC) in a total volume of 150ul. Proliferation or inhibition is quantitated by a 20 h pulse (1uCi/well) with 3H-thymidine (6.7 Ci/mM) beginning 72 h post factoraddition. The positive and negative controls are IL2 and mediumrespectively.

In vivo Assay—BALB/c mice are injected (i.p.) twice per day with bufferonly, or 2 mg/Kg of agonists or antagonists of the invention, ortruncated forms thereof. Mice receive this treatment for 4 consecutivedays, at which time they are sacrificed and various tissues and serumcollected for analyses. Comparison of H&E sections from normal spleensand spleens treated with agonists or antagonists of the inventionidentify the results of the activity of the agonists or antagonists onspleen cells, such as the diffusion of peri-arterial lymphatic sheaths,and/or significant increases in the nucleated cellularity of the redpulp regions, which may indicate the activation of the differentiationand proliferation of B-cell populations. Immunohistochemical studiesusing a B cell marker, anti-CD45R(B220), are used to determine whetherany physiological changes to splenic cells, such as splenicdisorganization, are due to increased B-cell representation withinloosely defined B-cell zones that infiltrate established T-cell regions.

Flow cytometric analyses of the spleens from mice treated with agonistor antagonist is used to indicate whether the agonists or antagonistsspecifically increases the proportion of ThB+, CD45R(B220) dull B cellsover that which is observed in control mice.

Likewise, a predicted consequence of increased mature B-cellrepresentation in vivo is a relative increase in serum Ig titers.Accordingly, serum IgM and IgA levels are compared between buffer andagonists or antagonists-treated mice.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 22 T Cell Proliferation Assay

A CD3-induced proliferation assay is performed on PBMCs and is measuredby the uptake of ³H-thymidine. The assay is performed as follows.Ninety-six well plates are coated with 100 μl/well of mAb to CD3 (HIT3a,Pharmingen) or isotype-matched control mAb (B33.1) overnight at 4degrees C. (1 μg/ml in 0.05M bicarbonate buffer, pH 9.5), then washedthree times with PBS. PBMC are isolated by F/H gradient centrifugationfrom human peripheral blood and added to quadruplicate wells(5×10⁴/well) of mAb coated plates in RPMI containing 10% FCS and P/S inthe presence of varying concentrations of agonists or antagonists of theinvention (total volume 200 ul). Relevant protein buffer and mediumalone are controls. After 48 hr. culture at 37 degrees C., plates arespun for 2 min. at 1000 rpm and 100 μl of supernatant is removed andstored −20 degrees C. for measurement of IL-2 (or other cytokines) ifeffect on proliferation is observed. Wells are supplemented with 100 ulof medium containing 0.5 uCi of ³H-thymidine and cultured at 37 degreesC. for 18-24 hr. Wells are harvested and incorporation of ³H-thymidineused as a measure of proliferation. Anti-CD3 alone is the positivecontrol for proliferation. IL-2 (100 U/ml) is also used as a controlwhich enhances proliferation. Control antibody which does not induceproliferation of T cells is used as the negative control for the effectsof agonists or antagonists of the invention.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 23 Effect of Agonists or Antagonists of the Invention on theExpression of MHC Class II, Costimulatory and Adhesion Molecules andCell Differentiation of Monocytes and Monocyte-Derived Human DendriticCells

Dendritic cells are generated by the expansion of proliferatingprecursors found in the peripheral blood: adherent PBMC or elutriatedmonocytic fractions are cultured for 7-10 days with GM-CSF (50 ng/ml)and IL-4 (20 ng/ml). These dendritic cells have the characteristicphenotype of immature cells (expression of CD1, CD80, CD86, CD40 and MHCclass II antigens). Treatment with activating factors, such as TNF-α,causes a rapid change in surface phenotype (increased expression of MHCclass I and II, costimulatory and adhesion molecules, downregulation ofFCγ RII, upregulation of CD83). These changes correlate with increasedantigen-presenting capacity and with functional maturation of thedendritic cells.

FACS analysis of surface antigens is performed as follows. Cells aretreated 1-3 days with increasing concentrations of agonist or antagonistof the invention or LPS (positive control), washed with PBS containing1% BSA and 0.02 mM sodium azide, and then incubated with 1:20 dilutionof appropriate FITC- or PE-labeled monoclonal antibodies for 30 minutesat 4 degrees C. After an additional wash, the labeled cells are analyzedby flow cytometry on a FACScan (Becton Dickinson).

Effect on the production of cytokines. Cytokines generated by dendriticcells, in particular IL-12, are important in the initiation of T-celldependent immune responses. IL-12 strongly influences the development ofThl helper T-cell immune response, and induces cytotoxic T and NK cellfunction. An ELISA is used to measure the IL-12 release as follows.Dendritic cells (10⁶/ml) are treated with increasing concentrations ofagonists or antagonists of the invention for 24 hours. LPS (100 ng/ml)is added to the cell culture as positive control. Supernatants from thecell cultures are then collected and analyzed for IL-12 content usingcommercial ELISA kit (e.g., R & D Systems (Minneapolis, Minn.)). Thestandard protocols provided with the kits are used.

Effect on the expression of MHC Class II, costimulatory and adhesionmolecules. Three major families of cell surface antigens can beidentified on monocytes: adhesion molecules, molecules involved inantigen presentation, and Fc receptor. Modulation of the expression ofMHC class II antigens and other costimulatory molecules, such as B7 andICAM-1, may result in changes in the antigen presenting capacity ofmonocytes and ability to induce T cell activation. Increased expressionof Fc receptors may correlate with improved monocyte cytotoxic activity,cytokine release and phagocytosis.

FACS analysis is used to examine the surface antigens as follows.Monocytes are treated 1-5 days with increasing concentrations ofagonists or antagonists of the invention or LPS (positive control),washed with PBS containing 1% BSA and 0.02 mM sodium azide, and thenincubated with 1:20 dilution of appropriate FITC- or PE-labeledmonoclonal antibodies for 30 minutes at 4 degrees C. After an additionalwash, the labeled cells are analyzed by flow cytometry on a FACScan(Becton Dickinson).

Monocyte activation and/or increased survival. Assays for molecules thatactivate (or alternatively, inactivate) monocytes and/or increasemonocyte survival (or alternatively, decrease monocyte survival) areknown in the art and may routinely be applied to determine whether amolecule of the invention functions as an inhibitor or activator ofmonocytes. Agonists or antagonists of the invention can be screenedusing the three assays described below. For each of these assays,Peripheral blood mononuclear cells (PBMC) are purified from single donorleukopacks (American Red Cross, Baltimore, Md.) by centrifugationthrough a Histopaque gradient (Sigma). Monocytes are isolated from PBMCby counterflow centrifugal elutriation.

Monocyte Survival Assay. Human peripheral blood monocytes progressivelylose viability when cultured in absence of serum or other stimuli. Theirdeath results from internally regulated processes (apoptosis). Additionto the culture of activating factors, such as TNF-alpha dramaticallyimproves cell survival and prevents DNA fragmentation. Propidium iodide(PI) staining is used to measure apoptosis as follows. Monocytes arecultured for 48 hours in polypropylene tubes in serum-free medium(positive control), in the presence of 100 ng/ml TNF-alpha (negativecontrol), and in the presence of varying concentrations of the compoundto be tested. Cells are suspended at a concentration of 2×10⁶/ml in PBScontaining PI at a final concentration of 5 μg/ml, and then incubated atroom temperature for 5 minutes before FACScan analysis. PI uptake hasbeen demonstrated to correlate with DNA fragmentation in thisexperimental paradigm.

Effect on cytokine release. An important function ofmonocytes/macrophages is their regulatory activity on other cellularpopulations of the immune system through the release of cytokines afterstimulation. An ELISA to measure cytokine release is performed asfollows. Human monocytes are incubated at a density of 5×10⁵ cells/mlwith increasing concentrations of agonists or antagonists of theinvention and under the same conditions, but in the absence of agonistsor antagonists. For IL-12 production, the cells are primed overnightwith IFN (100 U/ml) in the presence of agonist or antagonist of theinvention. LPS (10 ng/ml) is then added. Conditioned media are collectedafter 24 h and kept frozen until use. Measurement of TNF-alpha, IL-10,MCP-1 and IL-8 is then performed using a commercially available ELISAkit (e.g., R & D Systems (Minneapolis, Minn.)) and applying the standardprotocols provided with the kit.

Oxidative burst. Purified monocytes are plated in 96-w plate at 2-1×10⁵cell/well. Increasing concentrations of agonists or antagonists of theinvention are added to the wells in a total volume of 0.2 ml culturemedium (RPMI 1640+10% FCS, glutamine and antibiotics). After 3 daysincubation, the plates are centrifuged and the medium is removed fromthe wells. To the macrophage monolayers, 0.2 ml per well of phenol redsolution (140 mM NaCl, 10 mM potassium phosphate buffer pH 7.0, 5.5 mMdextrose, 0.56 mM phenol red and 19 U/ml of HRPO) is added, togetherwith the stimulant (200 nM PMA). The plates are incubated at 37° C. for2 hours and the reaction is stopped by adding 20 μl 1N NaOH per well.The absorbance is read at 610 nm. To calculate the amount of H₂O₂produced by the macrophages, a standard curve of a H₂O₂ solution ofknown molarity is performed for each experiment.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 24 Biological Effects of Agonists or Antagonists of theInvention

Astrocyte and Neuronal Assays

Agonists or antagonists of the invention, expressed in Escherichia coliand purified as described above, can be tested for activity in promotingthe survival, neurite outgrowth, or phenotypic differentiation ofcortical neuronal cells and for inducing the proliferation of glialfibrillary acidic protein immunopositive cells, astrocytes. Theselection of cortical cells for the bioassay is based on the prevalentexpression of FGF-1 and FGF-2 in cortical structures and on thepreviously reported enhancement of cortical neuronal survival resultingfrom FGF-2 treatment. A thymidine incorporation assay, for example, canbe used to elucidate an agonist or antagonist of the invention'sactivity on these cells.

Moreover, previous reports describing the biological effects of FGF-2(basic FGF) on cortical or hippocampal neurons in vitro havedemonstrated increases in both neuron survival and neurite outgrowth(Walicke et al., “Fibroblast growth factor promotes survival ofdissociated hippocampal neurons and enhances neurite extension.” Proc.Natl. Acad. Sci. USA 83:3012-3016. (1986), assay herein incorporated byreference in its entirety). However, reports from experiments done onPC-12 cells suggest that these two responses are not necessarilysynonymous and may depend on not only which FGF is being tested but alsoon which receptor(s) are expressed on the target cells. Using theprimary cortical neuronal culture paradigm, the ability of an agonist orantagonist of the invention to induce neurite outgrowth can be comparedto the response achieved with FGF-2 using, for example, a thymidineincorporation assay.

Fibroblast and Endothelial Cell Assays

Human lung fibroblasts are obtained from Clonetics (San Diego, Calif.)and maintained in growth media from Clonetics. Dermal microvascularendothelial cells are obtained from Cell Applications (San Diego,Calif.). For proliferation assays, the human lung fibroblasts and dermalmicrovascular endothelial cells can be cultured at 5,000 cells/well in a96-well plate for one day in growth medium. The cells are then incubatedfor one day in 0.1% BSA basal medium. After replacing the medium withfresh 0.1% BSA medium, the cells are incubated with the test proteinsfor 3 days. Alamar Blue (Alamar Biosciences, Sacramento, Calif.) isadded to each well to a final concentration of 10%. The cells areincubated for 4 hr. Cell viability is measured by reading in a CytoFluorfluorescence reader. For the PGE₂ assays, the human lung fibroblasts arecultured at 5,000 cells/well in a 96-well plate for one day. After amedium change to 0.1% BSA basal medium, the cells are incubated withFGF-2 or agonists or antagonists of the invention with or without IL-1αfor 24 hours. The supernatants are collected and assayed for PGE₂ by EIAkit (Cayman, Ann Arbor, Mich.). For the IL-6 assays, the human lungfibroblasts are cultured at 5,000 cells/well in a 96-well plate for oneday. After a medium change to 0.1% BSA basal medium, the cells areincubated with FGF-2 or with or without agonists or antagonists of theinvention IL-1a for 24 hours. The supernatants are collected and assayedfor IL-6 by ELISA kit (Endogen, Cambridge, Mass.).

Human lung fibroblasts are cultured with FGF-2 or agonists orantagonists of the invention for 3 days in basal medium before theaddition of Alamar Blue to assess effects on growth of the fibroblasts.FGF-2 should show a stimulation at 10-2500 ng/ml which can be used tocompare stimulation with agonists or antagonists of the invention.

Parkinson Models.

The loss of motor function in Parkinson's disease is attributed to adeficiency of striatal dopamine resulting from the degeneration of thenigrostriatal dopaminergic projection neurons. An animal model forParkinson's that has been extensively characterized involves thesystemic administration of 1-methyl-4 phenyl 1,2,3,6-tetrahydropyridine(MPTP). In the CNS, MPTP is taken-up by astrocytes and catabolized bymonoamine oxidase B to 1-methyl-4-phenyl pyridine (MPP⁺) and released.Subsequently, MPP⁺ is actively accumulated in dopaminergic neurons bythe high-affinity reuptake transporter for dopamine. MPP⁺ is thenconcentrated in mitochondria by the electrochemical gradient andselectively inhibits nicotidamide adenine disphosphate: ubiquinoneoxidoreductionase (complex I), thereby interfering with electrontransport and eventually generating oxygen radicals.

It has been demonstrated in tissue culture paradigms that FGF-2 (basicFGF) has trophic activity towards nigral dopaminergic neurons (Ferrariet al., Dev. Biol. 1989). Recently, Dr. Unsicker's group hasdemonstrated that administering FGF-2 in gel foam implants in thestriatum results in the near complete protection of nigral dopaminergicneurons from the toxicity associated with MPTP exposure (Otto andUnsicker, J. Neuroscience, 1990).

Based on the data with FGF-2, agonists or antagonists of the inventioncan be evaluated to determine whether it has an action similar to thatof FGF-2 in enhancing dopaminergic neuronal survival in vitro and it canalso be tested in vivo for protection of dopaminergic neurons in thestriatum from the damage associated with MPTP treatment. The potentialeffect of an agonist or antagonist of the invention is first examined invitro in a dopaminergic neuronal cell culture paradigm. The cultures areprepared by dissecting the midbrain floor plate from gestation day 14Wistar rat embryos. The tissue is dissociated with trypsin and seeded ata density of 200,000 cells/cm² on polyorthinine-laminin coated glasscoverslips. The cells are maintained in Dulbecco's Modified Eagle'smedium and F12 medium containing hormonal supplements (N1). The culturesare fixed with paraformaldehyde after 8 days in vitro and are processedfor tyrosine hydroxylase, a specific marker for dopaminergic neurons,immunohistochemical staining. Dissociated cell cultures are preparedfrom embryonic rats. The culture medium is changed every third day andthe factors are also added at that time.

Since the dopaminergic neurons are isolated from animals at gestationday 14, a developmental time which is past the stage when thedopaminergic precursor cells are proliferating, an increase in thenumber of tyrosine hydroxylase immunopositive neurons would represent anincrease in the number of dopaminergic neurons surviving in vitro.Therefore, if an agonist or antagonist of the invention acts to prolongthe survival of dopaminergic neurons, it would suggest that the agonistor antagonist may be involved in Parkinson's Disease.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 25 The Effect of Agonists or Antagonists of the Invention on theGrowth of Vascular Endothelial Cells

On day 1, human umbilical vein endothelial cells (HUVEC) are seeded at2-5×10⁴ cells/35 mm dish density in M199 medium containing 4% fetalbovine serum (FBS), 16 units/ml heparin, and 50 units/ml endothelialcell growth supplements (ECGS, Biotechnique, Inc.). On day 2, the mediumis replaced with M199 containing 10% FBS, 8 units/ml heparin. An agonistor antagonist of the invention, and positive controls, such as VEGF andbasic FGF (bFGF) are added, at varying concentrations. On days 4 and 6,the medium is replaced. On day 8, cell number is determined with aCoulter Counter.

An increase in the number of HUVEC cells indicates that the compound ofthe invention may proliferate vascular endothelial cells, while adecrease in the number of HUVEC cells indicates that the compound of theinvention inhibits vascular endothelial cells.

The studies described in this example tested activity of a polypeptideof the invention. However, one skilled in the art could easily modifythe exemplified studies to test the activity of polynucleotides (e.g.,gene therapy), agonists, and/or antagonists of the invention.

Example 26 Rat Corneal Wound Healing Model

This animal model shows the effect of an agonist or antagonist of theinvention on neovascularization. The experimental protocol includes:

a) Making a 1-1.5 mm long incision from the center of cornea into thestromal layer.

b) Inserting a spatula below the lip of the incision facing the outercorner of the eye.

c) Making a pocket (its base is 1-1.5 mm form the edge of the eye).

d) Positioning a pellet, containing 50 ng-5 ug of an agonist orantagonist of the invention, within the pocket.

e) Treatment with an agonist or antagonist of the invention can also beapplied topically to the corneal wounds in a dosage range of 20 mg-500mg (daily treatment for five days).

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 27 Diabetic Mouse and Glucocorticoid-Impaired Wound HealingModels

Diabetic db+/db+Mouse Model.

To demonstrate that an agonist or antagonist of the inventionaccelerates the healing process, the genetically diabetic mouse model ofwound healing is used. The full thickness wound healing model in thedb+/db+mouse is a well characterized, clinically relevant andreproducible model of impaired wound healing. Healing of the diabeticwound is dependent on formation of granulation tissue andre-epithelialization rather than contraction (Gartner, M. H. et al., J.Surg. Res. 52:389 (1992); Greenhalgh, D. G. et al., Am. J. Pathol.136:1235 (1990)).

The diabetic animals have many of the characteristic features observedin Type II diabetes mellitus. Homozygous (db+/db+) mice are obese incomparison to their normal heterozygous (db+/+m) littermates. Mutantdiabetic (db+/db+) mice have a single autosomal recessive mutation onchromosome 4 (db+) (Coleman et al. Proc. Natl. Acad. Sci. USA 77:283-293(1982)). Animals show polyphagia, polydipsia and polyuria. Mutantdiabetic mice (db+/db+) have elevated blood glucose, increased or normalinsulin levels, and suppressed cell-mediated immunity (Mandel et al., J.Immunol. 120:1375 (1978); Debray-Sachs, M. et al., Clin. Exp. Immunol.51(1):1-7 (1983); Leiter et al., Am. J. of Pathol. 114:46-55 (1985)).Peripheral neuropathy, myocardial complications, and microvascularlesions, basement membrane thickening and glomerular filtrationabnormalities have been described in these animals (Norido, F. et al.,Exp. Neurol. 83(2):221-232 (1984); Robertson et al., Diabetes29(1):60-67 (1980); Giacomelli et al., Lab Invest. 40(4):460-473 (1979);Coleman, D. L., Diabetes 31 (Suppl):1-6 (1982)). These homozygousdiabetic mice develop hyperglycemia that is resistant to insulinanalogous to human type II diabetes (Mandel et al., J. Immunol.120:1375-1377 (1978)).

The characteristics observed in these animals suggests that healing inthis model may be similar to the healing observed in human diabetes(Greenhalgh, et al., Am. J. of Pathol. 136:1235-1246 (1990)).

Genetically diabetic female C57BL/KsJ (db+/db+) mice and theirnon-diabetic (db+/+m) heterozygous littermates are used in this study(Jackson Laboratories). The animals are purchased at 6 weeks of age andare 8 weeks old at the beginning of the study. Animals are individuallyhoused and received food and water ad libitum. All manipulations areperformed using aseptic techniques. The experiments are conductedaccording to the rules and guidelines of Human Genome Sciences, Inc.Institutional Animal Care and Use Committee and the Guidelines for theCare and Use of Laboratory Animals.

Wounding protocol is performed according to previously reported methods(Tsuboi, R. and Rifkin, D. B., J. Exp. Med. 172:245-251 (1990)).Briefly, on the day of wounding, animals are anesthetized with anintraperitoneal injection of Avertin (0.01 mg/mL), 2,2,2-tribromoethanoland 2-methyl-2-butanol dissolved in deionized water. The dorsal regionof the animal is shaved and the skin washed with 70% ethanol solutionand iodine. The surgical area is dried with sterile gauze prior towounding. An 8 mm full-thickness wound is then created using a Keyestissue punch. Immediately following wounding, the surrounding skin isgently stretched to eliminate wound expansion. The wounds are left openfor the duration of the experiment. Application of the treatment isgiven topically for 5 consecutive days commencing on the day ofwounding. Prior to treatment, wounds are gently cleansed with sterilesaline and gauze sponges.

Wounds are visually examined and photographed at a fixed distance at theday of surgery and at two day intervals thereafter. Wound closure isdetermined by daily measurement on days 1-5 and on day 8. Wounds aremeasured horizontally and vertically using a calibrated Jameson caliper.Wounds are considered healed if granulation tissue is no longer visibleand the wound is covered by a continuous epithelium.

An agonist or antagonist of the invention is administered using at arange different doses, from 4 mg to 500 mg per wound per day for 8 daysin vehicle. Vehicle control groups received 50 mL of vehicle solution.

Animals are euthanized on day 8 with an intraperitoneal injection ofsodium pentobarbital (300 mg/kg). The wounds and surrounding skin arethen harvested for histology and immunohistochemistry. Tissue specimensare placed in 10% neutral buffered formalin in tissue cassettes betweenbiopsy sponges for further processing.

Three groups of 10 animals each (5 diabetic and 5 non-diabetic controls)are evaluated: 1) Vehicle placebo control, 2) untreated group, and 3)treated group.

Wound closure is analyzed by measuring the area in the vertical andhorizontal axis and obtaining the total square area of the wound.Contraction is then estimated by establishing the differences betweenthe initial wound area (day 0) and that of post treatment (day 8). Thewound area on day 1 is 64 mm², the corresponding size of the dermalpunch. Calculations are made using the following formula:[Open area on day 8]−[Open area on day 1]/[Open area on day 1]

Specimens are fixed in 10% buffered formalin and paraffin embeddedblocks are sectioned perpendicular to the wound surface (5 mm) and cutusing a Reichert-Jung microtome. Routine hematoxylin-eosin (H&E)staining is performed on cross-sections of bisected wounds. Histologicexamination of the wounds are used to assess whether the healing processand the morphologic appearance of the repaired skin is altered bytreatment with an agonist or antagonist of the invention. Thisassessment included verification of the presence of cell accumulation,inflammatory cells, capillaries, fibroblasts, re-epithelialization andepidermal maturity (Greenhalgh, D. G. et al., Am. J. Pathol. 136:1235(1990)). A calibrated lens micrometer is used by a blinded observer.

Tissue sections are also stained immunohistochemically with a polyclonalrabbit anti-human keratin antibody using ABC Elite detection system.Human skin is used as a positive tissue control while non-immune IgG isused as a negative control. Keratinocyte growth is determined byevaluating the extent of reepithelialization of the wound using acalibrated lens micrometer.

Proliferating cell nuclear antigen/cyclin (PCNA) in skin specimens isdemonstrated by using anti-PCNA antibody (1:50) with an ABC Elitedetection system. Human colon cancer served as a positive tissue controland human brain tissue is used as a negative tissue control. Eachspecimen included a section with omission of the primary antibody andsubstitution with non-immune mouse IgG. Ranking of these sections isbased on the extent of proliferation on a scale of 0-8, the lower sideof the scale reflecting slight proliferation to the higher sidereflecting intense proliferation.

Experimental data are analyzed using an unpaired t test. A p value of<0.05 is considered significant.

Steroid Impaired Rat Model

The inhibition of wound healing by steroids has been well documented invarious in vitro and in vivo systems (Wahl, Glucocorticoids and Woundhealing. In: Anti-Inflammatory Steroid Action: Basic and ClinicalAspects. 280-302 (1989); Wahl et al., J. Immunol. 115: 476-481 (1975);Werb et al., J. Exp. Med. 147:1684-1694 (1978)). Glucocorticoids retardwound healing by inhibiting angiogenesis, decreasing vascularpermeability (Ebert et al., An. Intern. Med. 37:701-705 (1952)),fibroblast proliferation, and collagen synthesis (Beck et al., GrowthFactors. 5: 295-304 (1991); Haynes et al., J. Clin. Invest. 61: 703-797(1978)) and producing a transient reduction of circulating monocytes(Haynes et al., J. Clin. Invest. 61: 703-797 (1978); Wahl,“Glucocorticoids and wound healing”, In: Antiinflammatory SteroidAction: Basic and Clinical Aspects, Academic Press, New York, pp.280-302 (1989)). The systemic administration of steroids to impairedwound healing is a well establish phenomenon in rats (Beck et al.,Growth Factors. 5: 295-304 (1991); Haynes et al., J. Clin. Invest. 61:703-797 (1978); Wahl, “Glucocorticoids and wound healing”, In:Antiinflammatory Steroid Action: Basic and Clinical Aspects, AcademicPress, New York, pp. 280-302 (1989); Pierce et al., Proc. Natl. Acad.Sci. USA 86: 2229-2233 (1989)).

To demonstrate that an agonist or antagonist of the invention canaccelerate the healing process, the effects of multiple topicalapplications of the agonist or antagonist on full thickness excisionalskin wounds in rats in which healing has been impaired by the systemicadministration of methylprednisolone is assessed.

Young adult male Sprague Dawley rats weighing 250-300 g (Charles RiverLaboratories) are used in this example. The animals are purchased at 8weeks of age and are 9 weeks old at the beginning of the study. Thehealing response of rats is impaired by the systemic administration ofmethylprednisolone (17 mg/kg/rat intramuscularly) at the time ofwounding. Animals are individually housed and received food and water adlibitum. All manipulations are performed using aseptic techniques. Thisstudy is conducted according to the rules and guidelines of Human GenomeSciences, Inc. Institutional Animal Care and Use Committee and theGuidelines for the Care and Use of Laboratory Animals.

The wounding protocol is followed according to section A, above. On theday of wounding, animals are anesthetized with an intramuscularinjection of ketamine (50 mg/kg) and xylazine (5 mg/kg). The dorsalregion of the animal is shaved and the skin washed with 70% ethanol andiodine solutions. The surgical area is dried with sterile gauze prior towounding. An 8 mm full-thickness wound is created using a Keyes tissuepunch. The wounds are left open for the duration of the experiment.Applications of the testing materials are given topically once a day for7 consecutive days commencing on the day of wounding and subsequent tomethylprednisolone administration. Prior to treatment, wounds are gentlycleansed with sterile saline and gauze sponges.

Wounds are visually examined and photographed at a fixed distance at theday of wounding and at the end of treatment. Wound closure is determinedby daily measurement on days 1-5 and on day 8. Wounds are measuredhorizontally and vertically using a calibrated Jameson caliper. Woundsare considered healed if granulation tissue is no longer visible and thewound is covered by a continuous epithelium.

The agonist or antagonist of the invention is administered using at arange different doses, from 4 mg to 500 mg per wound per day for 8 daysin vehicle. Vehicle control groups received 50 mL of vehicle solution.

Animals are euthanized on day 8 with an intraperitoneal injection ofsodium pentobarbital (300 mg/kg). The wounds and surrounding skin arethen harvested for histology. Tissue specimens are placed in 10% neutralbuffered formalin in tissue cassettes between biopsy sponges for furtherprocessing.

Three groups of 10 animals each (5 with methylprednisolone and 5 withoutglucocorticoid) are evaluated: 1) Untreated group 2) Vehicle placebocontrol 3) treated groups.

Wound closure is analyzed by measuring the area in the vertical andhorizontal axis and obtaining the total area of the wound. Closure isthen estimated by establishing the differences between the initial woundarea (day 0) and that of post treatment (day 8). The wound area on day 1is 64 mm², the corresponding size of the dermal punch. Calculations aremade using the following formula:[Open area on day 8]−[Open area on day 1]/[Open area on day 1]

Specimens are fixed in 10% buffered formalin and paraffin embeddedblocks are sectioned perpendicular to the wound surface (5 mm) and cutusing an Olympus microtome. Routine hematoxylin-eosin (H&E) staining isperformed on cross-sections of bisected wounds. Histologic examinationof the wounds allows assessment of whether the healing process and themorphologic appearance of the repaired skin is improved by treatmentwith an agonist or antagonist of the invention. A calibrated lensmicrometer is used by a blinded observer to determine the distance ofthe wound gap.

Experimental data are analyzed using an unpaired t test. A p value of<0.05 is considered significant.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 28 Lymphadema Animal Model

The purpose of this experimental approach is to create an appropriateand consistent lymphedema model for testing the therapeutic effects ofan agonist or antagonist of the invention in lymphangiogenesis andre-establishment of the lymphatic circulatory system in the rat hindlimb. Effectiveness is measured by swelling volume of the affected limb,quantification of the amount of lymphatic vasculature, total bloodplasma protein, and histopathology. Acute lymphedema is observed for7-10 days. Perhaps more importantly, the chronic progress of the edemais followed for up to 3-4 weeks.

Prior to beginning surgery, blood sample is drawn for proteinconcentration analysis. Male rats weighing approximately ˜350 g aredosed with Pentobarbital. Subsequently, the right legs are shaved fromknee to hip. The shaved area is swabbed with gauze soaked in 70% EtOH.Blood is drawn for serum total protein testing. Circumference andvolumetric measurements are made prior to injecting dye into paws aftermarking 2 measurement levels (0.5 cm above heel, at mid-pt of dorsalpaw). The intradermal dorsum of both right and left paws are injectedwith 0.05 ml of 1% Evan's Blue. Circumference and volumetricmeasurements are then made following injection of dye into paws.

Using the knee joint as a landmark, a mid-leg inguinal incision is madecircumferentially allowing the femoral vessels to be located. Forcepsand hemostats are used to dissect and separate the skin flaps. Afterlocating the femoral vessels, the lymphatic vessel that runs along sideand underneath the vessel(s) is located. The main lymphatic vessels inthis area are then electrically coagulated or suture ligated.

Using a microscope, muscles in back of the leg (near the semitendinosisand adductors) are bluntly dissected. The popliteal lymph node is thenlocated. The 2 proximal and 2 distal lymphatic vessels and distal bloodsupply of the popliteal node are then ligated by suturing. The popliteallymph node, and any accompanying adipose tissue, is then removed bycutting connective tissues.

Care is taken to control any mild bleeding resulting from thisprocedure. After lymphatics are occluded, the skin flaps are sealed byusing liquid skin (Vetbond) (AJ Buck). The separated skin edges aresealed to the underlying muscle tissue while leaving a gap of 0.5 cmaround the leg. Skin also may be anchored by suturing to underlyingmuscle when necessary.

To avoid infection, animals are housed individually with mesh (nobedding). Recovering animals are checked daily through the optimaledematous peak, which typically occurred by day 5-7. The plateauedematous peak are then observed. To evaluate the intensity of thelymphedema, the circumference and volumes of 2 designated places on eachpaw before operation and daily for 7 days are measured. The effect ofplasma proteins on lymphedema is determined and whether protein analysisis a useful testing perimeter is also investigated. The weights of bothcontrol and edematous limbs are evaluated at 2 places. Analysis isperformed in a blind manner.

Circumference Measurements: Under brief gas anesthetic to prevent limbmovement, a cloth tape is used to measure limb circumference.Measurements are done at the ankle bone and dorsal paw by 2 differentpeople and those 2 readings are averaged. Readings are taken from bothcontrol and edematous limbs.

Volumetric Measurements: On the day of surgery, animals are anesthetizedwith Pentobarbital and are tested prior to surgery. For dailyvolumetrics animals are under brief halothane anesthetic (rapidimmobilization and quick recovery), and both legs are shaved and equallymarked using waterproof marker on legs. Legs are first dipped in water,then dipped into instrument to each marked level then measured by Buxcoedema software (Chen/Victor). Data is recorded by one person, while theother is dipping the limb to marked area.

Blood-plasma protein measurements: Blood is drawn, spun, and serumseparated prior to surgery and then at conclusion for total protein andCa²⁺ comparison.

Limb Weight Comparison: After drawing blood, the animal is prepared fortissue collection. The limbs are amputated using a quillitine, then bothexperimental and control legs are cut at the ligature and weighed. Asecond weighing is done as the tibio-cacaneal joint is disarticulatedand the foot is weighed.

Histological Preparations: The transverse muscle located behind the knee(popliteal) area is dissected and arranged in a metal mold, filled withfreezeGel, dipped into cold methylbutane, placed into labeled samplebags at −80 EC until sectioning. Upon sectioning, the muscle is observedunder fluorescent microscopy for lymphatics.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 29 Suppression of TNF Alpha-Induced Adhesion Molecule Expressionby an Agonist or Antagonist of the Invention

The recruitment of lymphocytes to areas of inflammation and angiogenesisinvolves specific receptor-ligand interactions between cell surfaceadhesion molecules (CAMs) on lymphocytes and the vascular endothelium.The adhesion process, in both normal and pathological settings, followsa multi-step cascade that involves intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelialleukocyte adhesion molecule-1 (E-selectin) expression on endothelialcells (EC). The expression of these molecules and others on the vascularendothelium determines the efficiency with which leukocytes may adhereto the local vasculature and extravasate into the local tissue duringthe development of an inflammatory response. The local concentration ofcytokines and growth factor participate in the modulation of theexpression of these CAMs.

Tumor necrosis factor alpha (TNF-a), a potent proinflammatory cytokine,is a stimulator of all three CAMs on endothelial cells and may beinvolved in a wide variety of inflammatory responses, often resulting ina pathological outcome.

The potential of an agonist or antagonist of the invention to mediate asuppression of TNF-a induced CAM expression can be examined. A modifiedELISA assay which uses ECs as a solid phase absorbent is employed tomeasure the amount of CAM expression on TNF-a treated ECs whenco-stimulated with a member of the FGF family of proteins.

To perform the experiment, human umbilical vein endothelial cell (HUVEC)cultures are obtained from pooled cord harvests and maintained in growthmedium (EGM-2; Clonetics, San Diego, Calif.) supplemented with 10% FCSand 1% penicillin/streptomycin in a 37 degree C. humidified incubatorcontaining 5% CO₂. HUVECs are seeded in 96-well plates at concentrationsof 1×10⁴ cells/well in EGM medium at 37 degree C. for 18-24 hrs or untilconfluent. The monolayers are subsequently washed 3 times with aserum-free solution of RPMI-1640 supplemented with 100 U/ml penicillinand 100 mg/ml streptomycin, and treated with a given cytokine and/orgrowth factor(s) for 24 h at 37 degree C. Following incubation, thecells are then evaluated for CAM expression.

Human Umbilical Vein Endothelial cells (HUVECs) are grown in a standard96 well plate to confluence. Growth medium is removed from the cells andreplaced with 90 ul of 199 Medium (10% FBS). Samples for testing andpositive or negative controls are added to the plate in triplicate (in10 ul volumes). Plates are incubated at 37 degree C. for either 5 h(selectin and integrin expression) or 24 h (integrin expression only).Plates are aspirated to remove medium and 100 μl of 0.1%paraformaldehyde-PBS (with Ca++ and Mg++) is added to each well. Platesare held at 4° C. for 30 min.

Fixative is then removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. Do not allow the wells to dry. Add 10 μlof diluted primary antibody to the test and control wells.Anti-ICAM-1-Biotin, Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin areused at a concentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stockantibody). Cells are incubated at 37° C. for 30 min. in a humidifiedenvironment. Wells are washed X3 with PBS (+Ca,Mg)+0.5% BSA.

Then add 20 μl of diluted ExtrAvidin-Alkaline Phosphotase (1:5,000dilution) to each well and incubated at 37° C. for 30 min. Wells arewashed X3 with PBS (+Ca,Mg)+0.5% BSA. 1 tablet of p-NitrophenolPhosphate pNPP is dissolved in 5 ml of glycine buffer (pH 10.4). 100 μlof pNPP substrate in glycine buffer is added to each test well. Standardwells in triplicate are prepared from the working dilution of theExtrAvidin-Alkaline Phosphotase in glycine buffer: 1:5,000(10⁰)>10^(−0.5)>10⁻¹>10^(−1.5)0.5 μl of each dilution is added totriplicate wells and the resulting AP content in each well is 5.50 ng,1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent must then be added toeach of the standard wells. The plate must be incubated at 37° C. for 4h. A volume of 50 μl of 3M NaOH is added to all wells. The results arequantified on a plate reader at 405 nm. The background subtractionoption is used on blank wells filled with glycine buffer only. Thetemplate is set up to indicate the concentration of AP-conjugate in eachstandard well [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results areindicated as amount of bound AP-conjugate in each sample.

The studies described in this example tested activity of agonists orantagonists of the invention. However, one skilled in the art couldeasily modify the exemplified studies to test the activity ofpolynucleotides or polypeptides of the invention (e.g., gene therapy).

Example 30 Production Of Polypeptide of the Invention ForHigh-Throughput Screening Assays

The following protocol produces a supernatant containing polypeptide ofthe present invention to be tested. This supernatant can then be used inthe Screening Assays described in Examples 32-41.

First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution(1 mg/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516FBiowhittaker) for a working solution of 50 ug/ml. Add 200 ul of thissolution to each well (24 well plates) and incubate at RT for 20minutes. Be sure to distribute the solution over each well (note: a12-channel pipetter may be used with tips on every other channel).Aspirate off the Poly-D-Lysine solution and rinse with 1 ml PBS(Phosphate Buffered Saline). The PBS should remain in the well untiljust prior to plating the cells and plates may be poly-lysine coated inadvance for up to two weeks.

Plate 293T cells (do not carry cells past P+20) at 2×10⁵ cells/well in0.5 ml DMEM (Dulbecco's Modified Eagle Medium)(with 4.5 G/L glucose andL-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS (14-503FBiowhittaker)/1× Penstrep (17-602E Biowhittaker). Let the cells growovernight.

The next day, mix together in a sterile solution basin: 300 ulLipofectamine (18324-012 Gibco/BRL) and 5 ml Optimem I (31985070Gibco/BRL)/96-well plate. With a small volume multi-channel pipetter,aliquot approximately 2 ug of an expression vector containing apolynucleotide insert, produced by the methods described in Examples8-10, into an appropriately labeled 96-well round bottom plate. With amulti-channel pipetter, add 50 ul of the Lipofectamine/Optimem I mixtureto each well. Pipette up and down gently to mix. Incubate at RT 15-45minutes. After about 20 minutes, use a multi-channel pipetter to add 150ul Optimem I to each well. As a control, one plate of vector DNA lackingan insert should be transfected with each set of transfections.

Preferably, the transfection should be performed by tag-teaming thefollowing tasks. By tag-teaming, hands on time is cut in half, and thecells do not spend too much time on PBS. First, person A aspirates offthe media from four 24-well plates of cells, and then person B rinseseach well with 0.5-1 ml PBS. Person A then aspirates off PBS rinse, andperson B, using a12-channel pipetter with tips on every other channel,adds the 200 ul of DNA/Lipofectamine/Optimem I complex to the odd wellsfirst, then to the even wells, to each row on the 24-well plates.Incubate at 37 degree C. for 6 hours.

While cells are incubating, prepare appropriate media, either 1% BSA inDMEM with 1× penstrep, or HGS CHO-5 media (116.6 mg/L of CaCl₂ (anhyd);0.00130 mg/L CuSO₄-5H₂O; 0.050 mg/L of Fe(NO₃)₃-9H₂O; 0.417 mg/L ofFeSO₄.7H₂O; 311.80 mg/L of Kcl; 28.64 mg/L of MgCl₂; 48.84 mg/L ofMgSO₄; 6995.50 mg/L of NaCl; 2400.0 mg/L of NaHCO₃; 62.50 mg/L ofNaH₂PO₄—H₂O; 71.02 mg/L of Na₂HPO4; 0.4320 mg/L of ZnSO₄-7H₂O; 0.002mg/L of Arachidonic Acid; 1.022 mg/L of Cholesterol; 0.070 mg/L ofDL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid; 0.010 mg/L ofLinolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid;0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L ofPluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551mg/L of D-Glucose; 130.85 mg/ml of L-Alanine; 147.50 mg/ml ofL-Arginine-HCL; 7.50 mg/ml of L-Asparagine-H₂0; 6.65 mg/ml of L-AsparticAcid; 29.56 mg/ml of L-Cystine-2HCL-H₂0; 31.29 mg/ml of L-Cystine-2HCL;7.35 mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/mlof Glycine; 52.48 mg/ml of L-Histidine-HCL-H₂0; 106.97 mg/ml ofL-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of L-Lysine HCL;32.34 mg/ml of L-Methionine; 68.48 mg/ml of L-Phenylalainine; 40.0 mg/mlof L-Proline; 26.25 mg/ml of L-Serine; 101.05 mg/ml of L-Threonine;19.22 mg/ml of L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na-2H₂0; and99.65 mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-CaPantothenate; 11.78 mg/L of Choline Chloride; 4.65 mg/L of Folic Acid;15.60 mg/L of i-Inositol; 3.02 mg/L of Niacinamide; 3.00 mg/L ofPyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mg/L of Riboflavin;3.17 mg/L of Thiamine HCL; 0.365 mg/L of Thymidine; 0.680 mg/L ofVitamin B₁₂; 25 mM of HEPES Buffer; 2.39 mg/L of Na Hypoxanthine; 0.105mg/L of Lipoic Acid; 0.081 mg/L of Sodium Putrescine-2HCL; 55.0 mg/L ofSodium Pyruvate; 0.0067 mg/L of Sodium Selenite; 20 uM of Ethanolamine;0.122 mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrincomplexed with Linoleic Acid; 33.33 mg/L of Methyl-B-Cyclodextrincomplexed with Oleic Acid; 10 mg/L of Methyl-B-Cyclodextrin complexedwith Retinal Acetate. Adjust osmolarity to 327 mOsm) with 2 mm glutamineand 1× penstrep. (BSA (81-068-3 Bayer) 100 gm dissolved in IL DMEM for a10% BSA stock solution). Filter the media and collect 50 ul forendotoxin assay in 15 ml polystyrene conical.

The transfection reaction is terminated, preferably by tag-teaming, atthe end of the incubation period. Person A aspirates off thetransfection media, while person B adds 1.5 ml appropriate media to eachwell. Incubate at 37 degree C. for 45 or 72 hours depending on the mediaused: 1% BSA for 45 hours or CHO-5 for 72 hours.

On day four, using a 300 ul multichannel pipetter, aliquot 600 ul in one1 ml deep well plate and the remaining supernatant into a 2 ml deepwell. The supernatants from each well can then be used in the assaysdescribed in Examples 32-39.

It is specifically understood that when activity is obtained in any ofthe assays described below using a supernatant, the activity originatesfrom either the polypeptide of the present invention directly (e.g., asa secreted protein) or by polypeptide of the present invention inducingexpression of other proteins, which are then secreted into thesupernatant. Thus, the invention further provides a method ofidentifying the protein in the supernatant characterized by an activityin a particular assay.

Example 31 Construction of GAS Reporter Construct

One signal transduction pathway involved in the differentiation andproliferation of cells is called the Jaks-STATs pathway. Activatedproteins in the Jaks-STATs pathway bind to gamma activation site “GAS”elements or interferon-sensitive responsive element (“ISRE”), located inthe promoter of many genes. The binding of a protein to these elementsalter the expression of the associated gene.

GAS and ISRE elements are recognized by a class of transcription factorscalled Signal Transducers and Activators of Transcription, or “STATs.”There are six members of the STATs family. Stat1 and Stat3 are presentin many cell types, as is Stat2 (as response to IFN-alpha iswidespread). Stat4 is more restricted and is not in many cell typesthough it has been found in T helper class I, cells after treatment withIL-12. Stat5 was originally called mammary growth factor, but has beenfound at higher concentrations in other cells including myeloid cells.It can be activated in tissue culture cells by many cytokines.

The STATs are activated to translocate from the cytoplasm to the nucleusupon tyrosine phosphorylation by a set of kinases known as the JanusKinase (“Jaks”) family. Jaks represent a distinct family of solubletyrosine kinases and include Tyk2, Jak1, Jak2, and Jak3. These kinasesdisplay significant sequence similarity and are generally catalyticallyinactive in resting cells.

The Jaks are activated by a wide range of receptors summarized in theTable below. (Adapted from review by Schidler and Darnell, Ann. Rev.Biochem. 64:621-51 (1995)). A cytokine receptor family, capable ofactivating Jaks, is divided into two groups: (a) Class 1 includesreceptors for IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15,Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b)Class 2 includes IFN-a, IFN-g, and IL-10. The Class 1 receptors share aconserved cysteine motif (a set of four conserved cysteines and onetryptophan) and a WSXWS motif (a membrane proximal region encodingTrp-Ser-Xaa-Trp-Ser (SEQ ID NO: 2)).

Thus, on binding of a ligand to a receptor, Jaks are activated, which inturn activate STATs, which then translocate and bind to GAS elements.This entire process is encompassed in the Jaks-STATs signal transductionpathway. Therefore, activation of the Jaks-STATs pathway, reflected bythe binding of the GAS or the ISRE element, can be used to indicateproteins involved in the proliferation and differentiation of cells. Forexample, growth factors and cytokines are known to activate theJaks-STATs pathway (See Table below). Thus, by using GAS elements linkedto reporter molecules, activators of the Jaks-STATs pathway can beidentified. JAKs Ligand tyk2 Jak1 Jak2 Jak3 STATS GAS(elements) or ISREIFN family IFN-a/B + + − − 1, 2, 3 ISRE IFN-g + + − 1 GAS (IRF1 > Lys6 >IFP) Il-10 + ? ? − 1, 3 gp130 family IL-6 (Pleiotropic) + + + ? 1, 3 GAS(IRF1 > Lys6 > IFP) Il-11 (Pleiotropic) ? + ? ? 1, 3 OnM (Pleiotropic)? + + ? 1, 3 LIF (Pleiotropic) ? + + ? 1, 3 CNTF (Pleiotropic) −/+ + + ?1, 3 G-CSF (Pleiotropic) ? + ? ? 1, 3 IL-12 (Pleiotropic) + − + + 1, 3g-C family IL-2 (lymphocytes) − + − + 1, 3, 5 GAS IL-4 (lymph/myeloid)− + − + 6 GAS (IRF1 = IFP >> Ly6)(IgH) IL-7 (lymphocytes) − + − + 5 GASIL-9 (lymphocytes) − + − + 5 GAS IL-13 (lymphocyte) − + ? ? 6 GAS IL-15? + ? + 5 GAS gp140 family IL-3 (myeloid) − − + − 5 GAS (IRF1 > IFP >>Ly6) IL-5 (myeloid) − − + − 5 GAS GM-CSF (myeloid) − − + − 5 GAS Growthhormone family GH ? − + − 5 PRL ? +/− + − 1, 3, 5 EPO ? − + − 5GAS(B-CAS > IRF1 = IFP >> Ly6) Receptor Tyrosine Kinases EGF ? + + − 1,3 GAS (IRF1) PDGF ? + + − 1, 3 CSF-1 ? + + − 1, 3 GAS (not IRF1)

To construct a synthetic GAS containing promoter element, which is usedin the Biological Assays described in Examples 32-33, a PCR basedstrategy is employed to generate a GAS-SV40 promoter sequence. The 5′primer contains four tandem copies of the GAS binding site found in theIRF1 promoter and previously demonstrated to bind STATs upon inductionwith a range of cytokines (Rothman et al., Immunity 1:457-468 (1994).),although other GAS or ISRE elements can be used instead. The 5′ primeralso contains 18 bp of sequence complementary to the SV40 early promotersequence and is flanked with an XhoI site. The sequence of the 5′ primeris: 5′:GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCC (SEQ ID NO:3)CGAAATGATTTCCCCGAAATGATTTCCCCGAAATATC TGCCATCTCAATTAG:3′

The downstream primer is complementary to the SV40 promoter and isflanked with a Hind III site: 5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ IDNO: 4)

PCR amplification is performed using the SV40 promoter template presentin the B-gal:promoter plasmid obtained from Clontech. The resulting PCRfragment is digested with XhoI/Hind III and subcloned into BLSK2-.(Stratagene.) Sequencing with forward and reverse primers confirms thatthe insert contains the following sequence:5′:CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAA (SEQ ID NO:5)ATGATTTCCCCGAAATGATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGC TTTTGCAAAAAGCTT:3′

With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2reporter construct is next engineered. Here, the reporter molecule is asecreted alkaline phosphatase, or “SEAP.” Clearly, however, any reportermolecule can be instead of SEAP, in this or in any of the otherExamples. Well known reporter molecules that can be used instead of SEAPinclude chloramphenicol acetyltransferase (CAT), luciferase, alkalinephosphatase, B-galactosidase, green fluorescent protein (GFP), or anyprotein detectable by an antibody.

The above sequence confirmed synthetic GAS-SV40 promoter element issubcloned into the pSEAP-Promoter vector obtained from Clontech usingHindIII and XhoI, effectively replacing the SV40 promoter with theamplified GAS:SV40 promoter element, to create the GAS-SEAP vector.However, this vector does not contain a neomycin resistance gene, andtherefore, is not preferred for mammalian expression systems.

Thus, in order to generate mammalian stable cell lines expressing theGAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAPvector using SalI and NotI, and inserted into a backbone vectorcontaining the neomycin resistance gene, such as pGFP-1 (Clontech),using these restriction sites in the multiple cloning site, to createthe GAS-SEAP/Neo vector. Once this vector is transfected into mammaliancells, this vector can then be used as a reporter molecule for GASbinding as described in Examples 32-33.

Other constructs can be made using the above description and replacingGAS with a different promoter sequence. For example, construction ofreporter molecules containing EGR and NF-KB promoter sequences aredescribed in Examples 34 and 35. However, many other promoters can besubstituted using the protocols described in these Examples. Forinstance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted,alone or in combination (e.g., GAS/NF-KB/EGR, GAS/NF-KB, 11-2/NFAT, orNF-KB/GAS). Similarly, other cell lines can be used to test reporterconstruct activity, such as HELA (epithelial), HUVEC (endothelial), Reh(B-cell), Saos-2 (osteoblast), HUVAC (aortic), or Cardiomyocyte.

Example 32 High-Throughput Screening Assay for T-Cell Activity

The following protocol is used to assess T-cell activity by identifyingfactors, and determining whether supernate containing a polypeptide ofthe invention proliferates and/or differentiates T-cells. T-cellactivity is assessed using the GAS/SEAP/Neo construct produced inExample 31. Thus, factors that increase SEAP activity indicate theability to activate the Jaks-STATS signal transduction pathway. TheT-cell used in this assay is Jurkat T-cells (ATCC Accession No.TIB-152), although Molt-3 cells (ATCC Accession No. CRL-1552) and Molt-4cells (ATCC Accession No. CRL-1582) cells can also be used.

Jurkat T-cells are lymphoblastic CD4+ Th1 helper cells. In order togenerate stable cell lines, approximately 2 million Jurkat cells aretransfected with the GAS-SEAP/neo vector using DMRIE-C (LifeTechnologies)(transfection procedure described below). The transfectedcells are seeded to a density of approximately 20,000 cells per well andtransfectants resistant to 1 mg/ml genticin selected. Resistant coloniesare expanded and then tested for their response to increasingconcentrations of interferon gamma. The dose response of a selectedclone is demonstrated.

Specifically, the following protocol will yield sufficient cells for 75wells containing 200 ul of cells. Thus, it is either scaled up, orperformed in multiple to generate sufficient cells for multiple 96 wellplates. Jurkat cells are maintained in RPMI+10% serum with 1% Pen-Strep.Combine 2.5 mls of OPTI-MEM (Life Technologies) with 10 ug of plasmidDNA in a T25 flask. Add 2.5 ml OPTI-MEM containing 50 ul of DMRIE-C andincubate at room temperature for 15-45 mins.

During the incubation period, count cell concentration, spin down therequired number of cells (10⁷ per transfection), and resuspend inOPTI-MEM to a final concentration of 10⁷ cells/ml. Then add 1 ml of1×10⁷ cells in OPTI-MEM to T25 flask and incubate at 37 degree C. for 6hrs. After the incubation, add 10 ml of RPMI+15% serum.

The Jurkat:GAS-SEAP stable reporter lines are maintained in RPMI+10%serum, 1 mg/ml Genticin, and 1% Pen-Strep. These cells are treated withsupernatants containing polypeptide of the present invention orpolypeptide of the present invention induced polypeptides as produced bythe protocol described in Example 30.

On the day of treatment with the supernatant, the cells should be washedand resuspended in fresh RPMI+10% serum to a density of 500,000 cellsper ml. The exact number of cells required will depend on the number ofsupernatants being screened. For one 96 well plate, approximately 10million cells (for 10 plates, 100 million cells) are required.

Transfer the cells to a triangular reservoir boat, in order to dispensethe cells into a 96 well dish, using a 12 channel pipette. Using a 12channel pipette, transfer 200 ul of cells into each well (thereforeadding 100,000 cells per well).

After all the plates have been seeded, 50 ul of the supernatants aretransferred directly from the 96 well plate containing the supernatantsinto each well using a 12 channel pipette. In addition, a dose ofexogenous interferon gamma (0.1, 1.0, 10 ng) is added to wells H9, H10,and H11 to serve as additional positive controls for the assay.

The 96 well dishes containing Jurkat cells treated with supernatants areplaced in an incubator for 48 hrs (note: this time is variable between48-72 hrs). 35 ul samples from each well are then transferred to anopaque 96 well plate using a 12 channel pipette. The opaque platesshould be covered (using sellophene covers) and stored at −20 degree C.until SEAP assays are performed according to Example 36. The platescontaining the remaining treated cells are placed at 4 degree C. andserve as a source of material for repeating the assay on a specific wellif desired.

As a positive control, 100 Unit/ml interferon gamma can be used which isknown to activate Jurkat T cells. Over 30 fold induction is typicallyobserved in the positive control wells.

The above protocol may be used in the generation of both transient, aswell as, stable transfected cells, which would be apparent to those ofskill in the art.

Example 33 High-Throughput Screening Assay Identifying Myeloid Activity

The following protocol is used to assess myeloid activity of polypeptideof the present invention by determining whether polypeptide of thepresent invention proliferates and/or differentiates myeloid cells.Myeloid cell activity is assessed using the GAS/SEAP/Neo constructproduced in Example 31. Thus, factors that increase SEAP activityindicate the ability to activate the Jaks-STATS signal transductionpathway. The myeloid cell used in this assay is U937, a pre-monocytecell line, although TF-1, HL60, or KG1 can be used.

To transiently transfect U937 cells with the GAS/SEAP/Neo constructproduced in Example 31, a DEAE-Dextran method (Kharbanda et. al., 1994,Cell Growth & Differentiation, 5:259-265) is used. First, harvest 2×10⁷U937 cells and wash with PBS. The U937 cells are usually grown in RPMI1640 medium containing 10% heat-inactivated fetal bovine serum (FBS)supplemented with 100 units/ml penicillin and 100 mg/ml streptomycin.

Next, suspend the cells in 1 ml of 20 mM Tris-HCl (pH 7.4) buffercontaining 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid DNA, 140 mMNaCl, 5 mM KCl, 375 uM Na₂HPO₄.7H₂O, 1 mM MgCl₂, and 675 uM CaCl₂.Incubate at 37 degrees C. for 45 min.

Wash the cells with RPMI 1640 medium containing 10% FBS and thenresuspend in 10 ml complete medium and incubate at 37 degree C. for 36hr.

The GAS-SEAP/U937 stable cells are obtained by growing the cells in 400ug/ml G418. The G418-free medium is used for routine growth but everyone to two months, the cells should be re-grown in 400 ug/ml G418 forcouple of passages.

These cells are tested by harvesting 1×10⁸ cells (this is enough for ten96-well plates assay) and wash with PBS. Suspend the cells in 200 mlabove described growth medium, with a final density of 5×10⁵ cells/ml.Plate 200 ul cells per well in the 96-well plate (or 1×10⁵ cells/well).

Add 50 ul of the supernatant prepared by the protocol described inExample 30. Incubate at 37 degree C for 48 to 72 hr. As a positivecontrol, 100 Unit/ml interferon gamma can be used which is known toactivate U937 cells. Over 30 fold induction is typically observed in thepositive control wells. SEAP assay the supernatant according to theprotocol described in Example 36.

Example 34 High-Throughput Screening Assay Identifying Neuronal Activity

When cells undergo differentiation and proliferation, a group of genesare activated through many different signal transduction pathways. Oneof these genes, EGRL (early growth response gene 1), is induced invarious tissues and cell types upon activation. The promoter of EGR1 isresponsible for such induction. Using the EGR1 promoter linked toreporter molecules, activation of cells can be assessed by polypeptideof the present invention.

Particularly, the following protocol is used to assess neuronal activityin PC12 cell lines. PC12 cells (rat phenochromocytoma cells) are knownto proliferate and/or differentiate by activation with a number ofmitogens, such as TPA (tetradecanoyl phorbol acetate), NGF (nerve growthfactor), and EGF (epidermal growth factor). The EGR1 gene expression isactivated during this treatment. Thus, by stably transfecting PC12 cellswith a construct containing an EGR promoter linked to SEAP reporter,activation of PC12 cells by polypeptide of the present invention can beassessed.

The EGR/SEAP reporter construct can be assembled by the followingprotocol. The EGR-1 promoter sequence (−633 to +1)(Sakamoto K et al.,Oncogene 6:867-871 (1991)) can be PCR amplified from human genomic DNAusing the following primers: 5′ GCGCTCGAGGGATGACAGCGATAGAACCCCGG- (SEQID NO:6) 3′ 5′ GCGAAGCTTCGCGACTCCCCGGATCCGCCTC-3′ (SEQ ID NO:7)

Using the GAS:SEAP/Neo vector produced in Example 31, EGR1 amplifiedproduct can then be inserted into this vector. Linearize theGAS:SEAP/Neo vector using restriction enzymes XhoI/HindIII, removing theGAS/SV40 stuffer. Restrict the EGR1 amplified product with these sameenzymes. Ligate the vector and the EGR1 promoter.

To prepare 96 well-plates for cell culture, two mls of a coatingsolution (1:30 dilution of collagen type I (Upstate Biotech Inc.Cat#08-115) in 30% ethanol (filter sterilized)) is added per one 10 cmplate or 50 ml per well of the 96-well plate, and allowed to air dry for2 hr.

PC12 cells are routinely grown in RPMI-1640 medium (Bio Whittaker)containing 10% horse serum (JRH BIOSCIENCES, Cat. # 12449-78P), 5%heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/mlpenicillin and 100 ug/ml streptomycin on a precoated 10 cm tissueculture dish. One to four split is done every three to four days. Cellsare removed from the plates by scraping and resuspended with pipettingup and down for more than 15 times.

Transfect the EGR/SEAP/Neo construct into PC12 using the Lipofectamineprotocol described in Example 30. EGR-SEAP/PC12 stable cells areobtained by growing the cells in 300 ug/ml G418. The G418-free medium isused for routine growth but every one to two months, the cells should bere-grown in 300 ug/ml G418 for couple of passages.

To assay for neuronal activity, a 10 cm plate with cells around 70 to80% confluent is screened by removing the old medium. Wash the cellsonce with PBS (Phosphate buffered saline). Then starve the cells in lowserum medium (RPMI-1640 containing 1% horse serum and 0.5% FBS withantibiotics) overnight.

The next morning, remove the medium and wash the cells with PBS. Scrapeoff the cells from the plate, suspend the cells well in 2 ml low serummedium. Count the cell number and add more low serum medium to reachfinal cell density as 5×10⁵ cells/ml.

Add 200 ul of the cell suspension to each well of 96-well plate(equivalent to 1×10⁵ cells/well). Add 50 ul supernatant produced byExample 30, 37 degree C. for 48 to 72 hr. As a positive control, agrowth factor known to activate PC12 cells through EGR can be used, suchas 50 ng/ul of Neuronal Growth Factor (NGF). Over fifty-fold inductionof SEAP is typically seen in the positive control wells. SEAP assay thesupernatant according to Example 36.

Example 35 High-Throughput Screening Assay for T-Cell Activity

NF-KB (Nuclear Factor KB) is a transcription factor activated by a widevariety of agents including the inflammatory cytokines IL-1 and TNF,CD30 and CD40, lymphotoxin-alpha and lymphotoxin-beta, by exposure toLPS or thrombin, and by expression of certain viral gene products. As atranscription factor, NF-KB regulates the expression of genes involvedin immune cell activation, control of apoptosis (NF-KB appears to shieldcells from apoptosis), B and T-cell development, anti-viral andantimicrobial responses, and multiple stress responses.

In non-stimulated conditions, NF-KB is retained in the cytoplasm withI-KB (Inhibitor KB). However, upon stimulation, I-KB is phosphorylatedand degraded, causing NF-KB to shuttle to the nucleus, therebyactivating transcription of target genes. Target genes activated byNF-KB include IL-2, IL-6, GM-CSF, ICAM-1 and class 1 MHC.

Due to its central role and ability to respond to a range of stimuli,reporter constructs utilizing the NF-KB promoter element are used toscreen the supernatants produced in Example 30. Activators or inhibitorsof NF-KB would be useful in treating, preventing, and/or diagnosingdiseases. For example, inhibitors of NF-KB could be used to treat thosediseases related to the acute or chronic activation of NF-KB, such asrheumatoid arthritis.

To construct a vector containing the NF-KB promoter element, a PCR basedstrategy is employed. The upstream primer contains four tandem copies ofthe NF-KB binding site (GGGGACTTTCCC) (SEQ ID NO: 8), 18 bp of sequencecomplementary to the 5′ end of the SV40 early promoter sequence, and isflanked with an XhoI site: 5′:GCGGCCTCGAGGGGACTTTCCCGGGGACTTTCCG (SEQ IDNO:9) GGGACTTTCCGGGACTTTCCATCCTGCCATCTCAATT AG:3′

The downstream primer is complementary to the 3′ end of the SV40promoter and is flanked with a Hind III site:5′:GCGGCAAGCTTTTTGCAAAGCCTAGGC:3′ (SEQ ID NO:4)

PCR amplification is performed using the SV40 promoter template presentin the pB-gal:promoter plasmid obtained from Clontech. The resulting PCRfragment is digested with XhoI and Hind III and subcloned into BLSK2-.(Stratagene) Sequencing with the T7 and T3 primers confirms the insertcontains the following sequence: 5′:CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGA(SEQ ID NO:10) CTTTCCGGGACTTTCCATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAA AAAGCTT:3′

Next, replace the SV40 minimal promoter element present in thepSEAP2-promoter plasmid (Clontech) with this NF-KB/SV40 fragment usingXhoI and HindIII. However, this vector does not contain a neomycinresistance gene, and therefore, is not preferred for mammalianexpression systems.

In order to generate stable mammalian cell lines, the NF-KB/SV46/SEAPcassette is removed from the above NF-KB/SEAP vector using restrictionenzymes SalI and NotI, and inserted into a vector containing neomycinresistance. Particularly, the NF-KB/SV40/SEAP cassette was inserted intopGFP-1 (Clontech), replacing the GFP gene, after restricting pGFP-1 withSalI and NotI.

Once NF-KB/SV40/SEAP/Neo vector is created, stable Jurkat T-cells arecreated and maintained according to the protocol described in Example32. Similarly, the method for assaying supernatants with these stableJurkat T-cells is also described in Example 32. As a positive control,exogenous TNF alpha (0.1, 1, 10 ng) is added to wells H9, H10, and H11,with a 5-10 fold activation typically observed.

Example 36 Assay for SEAP Activity

As a reporter molecule for the assays described in Examples 32-35, SEAPactivity is assayed using the Tropix Phospho-light Kit (Cat. BP-400)according to the following general procedure. The Tropix Phospho-lightKit supplies the Dilution, Assay, and Reaction Buffers used below.

Prime a dispenser with the 2.5× Dilution Buffer and dispense 15 ul of2.5× dilution buffer into Optiplates containing 35 ul of a supernatant.Seal the plates with a plastic sealer and incubate at 65 degree C. for30 min. Separate the Optiplates to avoid uneven heating.

Cool the samples to room temperature for 15 minutes. Empty the dispenserand prime with the Assay Buffer. Add 50 ml Assay Buffer and incubate atroom temperature 5 min. Empty the dispenser and prime with the ReactionBuffer (see the Table below). Add 50 ul Reaction Buffer and incubate atroom temperature for 20 minutes. Since the intensity of thechemiluminescent signal is time dependent, and it takes about 10 minutesto read 5 plates on a luminometer, thus one should treat 5 plates ateach time and start the second set 10 minutes later.

Read the relative light unit in the luminometer. Set H12 as blank, andprint the results. An increase in chemiluminescence indicates reporteractivity. Reaction Buffer Formulation: # of plates Rxn buffer diluent(ml) CSPD (ml) 10 60 3 11 65 3.25 12 70 3.5 13 75 3.75 14 80 4 15 854.25 16 90 4.5 17 95 4.75 18 100 5 19 105 5.25 20 110 5.5 21 115 5.75 22120 6 23 125 6.25 24 130 6.5 25 135 6.75 26 140 7 27 145 7.25 28 150 7.529 155 7.75 30 160 8 31 165 8.25 32 170 8.5 33 175 8.75 34 180 9 35 1859.25 36 190 9.5 37 195 9.75 38 200 10 39 205 10.25 40 210 10.5 41 21510.75 42 220 11 43 225 11.25 44 230 11.5 45 235 11.75 46 240 12 47 24512.25 48 250 12.5 49 255 12.75 50 260 13

Example 37 High-Throughput Screening Assay Identifying Changes in SmallMolecule Concentration and Membrane Permeability

Binding of a ligand to a receptor is known to alter intracellular levelsof small molecules, such as calcium, potassium, sodium, and pH, as wellas alter membrane potential. These alterations can be measured in anassay to identify supernatants which bind to receptors of a particularcell. Although the following protocol describes an assay for calcium,this protocol can easily be modified to detect changes in potassium,sodium, pH, membrane potential, or any other small molecule which isdetectable by a fluorescent probe.

The following assay uses Fluorometric Imaging Plate Reader (“FLIPR”) tomeasure changes in fluorescent molecules (Molecular Probes) that bindsmall molecules. Clearly, any fluorescent molecule detecting a smallmolecule can be used instead of the calcium fluorescent molecule, fluo-4(Molecular Probes, Inc.; catalog no. F-14202), used here.

For adherent cells, seed the cells at 10,000 cells/well in a Co-starblack 96-well plate with clear bottom. The plate is incubated in a CO₂incubator for 20 hours. The adherent cells are washed two times inBiotek washer with 200 ul of HBSS (Hank's Balanced Salt Solution)leaving 100 ul of buffer after the final wash.

A stock solution of 1 mg/ml fluo-4 is made in 10% pluronic acid DMSO. Toload the cells with fluo-4, 50 ul of 12 ug/ml fluo-4 is added to eachwell. The plate is incubated at 37 degrees C. in a CO₂ incubator for 60min. The plate is washed four times in the Biotek washer with HBSSleaving 100 ul of buffer.

For non-adherent cells, the cells are spun down from culture media.Cells are re-suspended to 2-5×10⁶ cells/ml with HBSS in a 50-ml conicaltube. 4 ul of 1 mg/ml fluo-4 solution in 10% pluronic acid DMSO is addedto each ml of cell suspension. The tube is then placed in a 37 degreesC. water bath for 30-60 min. The cells are washed twice with HBSS,resuspended to 1×10⁶ cells/ml, and dispensed into a microplate, 100ul/well. The plate is centrifuged at 1000 rpm for 5 min. The plate isthen washed once in Denley Cell Wash with 200 ul, followed by anaspiration step to 100 ul final volume.

For a non-cell based assay, each well contains a fluorescent molecule,such as fluo-4. The supernatant is added to the well, and a change influorescence is detected.

To measure the fluorescence of intracellular calcium, the FLIPR is setfor the following parameters: (1) System gain is 300-800 mW; (2)Exposure time is 0.4 second; (3) Camera F/stop is F/2; (4) Excitation is488 nm; (5) Emission is 530 nm; and (6) Sample addition is 50 ul.Increased emission at 530 nm indicates an extracellular signaling eventcaused by the a molecule, either polypeptide of the present invention ora molecule induced by polypeptide of the present invention, which hasresulted in an increase in the intracellular Ca⁺⁺ concentration.

Example 38 High-Throughput Screening Assay Identifying Tyrosine KinaseActivity

The Protein Tyrosine Kinases (PTK) represent a diverse group oftransmembrane and cytoplasmic kinases. Within the Receptor ProteinTyrosine Kinase RPTK) group are receptors for a range of mitogenic andmetabolic growth factors including the PDGF, FGF, EGF, NGF, HGF andInsulin receptor subfamilies. In addition there are a large family ofRPTKs for which the corresponding ligand is unknown. Ligands for RPTKsinclude mainly secreted small proteins, but also membrane-bound andextracellular matrix proteins.

Activation of RPTK by ligands involves ligand-mediated receptordimerization, resulting in transphosphorylation of the receptor subunitsand activation of the cytoplasmic tyrosine kinases. The cytoplasmictyrosine kinases include receptor associated tyrosine kinases of thesrc-family (e.g., src, yes, lck, lyn, fyn) and non-receptor linked andcytosolic protein tyrosine kinases, such as the Jak family, members ofwhich mediate signal transduction triggered by the cytokine superfamilyof receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).

Because of the wide range of known factors capable of stimulatingtyrosine kinase activity, identifying whether polypeptide of the presentinvention or a molecule induced by polypeptide of the present inventionis capable of activating tyrosine kinase signal transduction pathways isof interest. Therefore, the following protocol is designed to identifysuch molecules capable of activating the tyrosine kinase signaltransduction pathways.

Seed target cells (e.g., primary keratinocytes) at a density ofapproximately 25,000 cells per well in a 96 well Loprodyne Silent ScreenPlates purchased from Nalge Nunc (Naperville, Ill.). The plates aresterilized with two 30 minute rinses with 100% ethanol, rinsed withwater and dried overnight. Some plates are coated for 2 hr with 100 mlof cell culture grade type I collagen (50 mg/ml), gelatin (2%) orpolylysine (50 mg/ml), all of which can be purchased from SigmaChemicals (St. Louis, Mo.) or 10% Matrigel purchased from BectonDickinson (Bedford, Mass.), or calf serum, rinsed with PBS and stored at4 degree C. Cell growth on these plates is assayed by seeding 5,000cells/well in growth medium and indirect quantitation of cell numberthrough use of alamarBlue as described by the manufacturer AlamarBiosciences, Inc. (Sacramento, Calif.) after 48 hr. Falcon plate covers#3071 from Becton Dickinson (Bedford, Mass.) are used to cover theLoprodyne Silent Screen Plates. Falcon Microtest III cell culture platescan also be used in some proliferation experiments.

To prepare extracts, A431 cells are seeded onto the nylon membranes ofLoprodyne plates (20,000/200 ml/well) and cultured overnight in completemedium. Cells are quiesced by incubation in serum-free basal medium for24 hr. After 5-20 minutes treatment with EGF (60 ng/ml) or 50 ul of thesupernatant produced in Example 30, the medium was removed and 100 ml ofextraction buffer ((20 mM HEPES pH 7.5, 0.15 M NaCl, 1% Triton X-100,0.1% SDS, 2 mM Na3VO4, 2 mM Na4P207 and a cocktail of proteaseinhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis,Ind.)) is added to each well and the plate is shaken on a rotatingshaker for 5 minutes at 4° C. The plate is then placed in a vacuumtransfer manifold and the extract filtered through the 0.45 mm membranebottoms of each well using house vacuum. Extracts are collected in a96-well catch/assay plate in the bottom of the vacuum manifold andimmediately placed on ice. To obtain extracts clarified bycentrifugation, the content of each well, after detergent solubilizationfor 5 minutes, is removed and centrifuged for 15 minutes at 4 degree C.at 16,000×g.

Test the filtered extracts for levels of tyrosine kinase activity.Although many methods of detecting tyrosine kinase activity are known,one method is described here.

Generally, the tyrosine kinase activity of a supernatant is evaluated bydetermining its ability to phosphorylate a tyrosine residue on aspecific substrate (a biotinylated peptide). Biotinylated peptides thatcan be used for this purpose include PSK1 (corresponding to amino acids6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding toamino acids 1-17 of gastrin). Both peptides are substrates for a rangeof tyrosine kinases and are available from Boehringer Mannheim.

The tyrosine kinase reaction is set up by adding the followingcomponents in order. First, add 10 ul of 5 uM Biotinylated Peptide, then10 ul ATP/IMg₂+(5 mM ATP/50 mM MgCl₂), then 10 ul of 5× Assay Buffer (40mM imidazole hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1 mMEGTA, 100 mM MgCl₂, 5 mM MnCl₂, 0.5 mg/ml BSA), then 5 ul of SodiumVanadate (1 mM), and then 5 ul of water. Mix the components gently andpreincubate the reaction mix at 30 degree C. for 2 min. Initial thereaction by adding 10 ul of the control enzyme or the filteredsupernatant.

The tyrosine kinase assay reaction is then terminated by adding 10 ul of120 mm EDTA and place the reactions on ice.

Tyrosine kinase activity is determined by transferring 50 ul aliquot ofreaction mixture to a microtiter plate (MTP) module and incubating at 37degree C. for 20 min. This allows the streptavidin coated 96 well plateto associate with the biotinylated peptide. Wash the MTP module with 300ul/well of PBS four times. Next add 75 ul of anti-phospotyrosineantibody conjugated to horse radish peroxidase (anti-P-Tyr-POD(0.5u/ml)) to each well and incubate at 37 degree C. for one hour. Washthe well as above.

Next add 100 ul of peroxidase substrate solution (Boehringer Mannheim)and incubate at room temperature for at least 5 mins (up to 30 min).Measure the absorbance of the sample at 405 nm by using ELISA reader.The level of bound peroxidase activity is quantitated using an ELISAreader and reflects the level of tyrosine kinase activity.

Example 39 High-Throughput Screening Assay Identifying PhosphorylationActivity

As a potential alternative and/or complement to the assay of proteintyrosine kinase activity described in Example 38, an assay which detectsactivation (phosphorylation) of major intracellular signal transductionintermediates can also be used. For example, as described below oneparticular assay can detect tyrosine phosphorylation of the Erk-1 andErk-2 kinases. However, phosphorylation of other molecules, such as Raf,JNK, p38. MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specifickinase (MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine,phosphotyrosine, or phosphothreonine molecule, can be detected bysubstituting these molecules for Erk-1 or Erk-2 in the following assay.

Specifically, assay plates are made by coating the wells of a 96-wellELISA plate with 0.1 ml of protein G (1 ug/ml) for 2 hr at room temp,(RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBSfor 1 hr at RT. The protein G plates are then treated with 2 commercialmonoclonal antibodies (10 ng/well) against Erk-1 and Erk-2 (1 hr at RT)(Santa Cruz Biotechnology). (To detect other molecules, this step caneasily be modified by substituting a monoclonal antibody detecting anyof the above described molecules.) After 3-5 rinses with PBS, the platesare stored at 4 degree C. until use.

A431 cells are seeded at 20,000/well in a 96-well Loprodyne filterplateand cultured overnight in growth medium. The cells are then starved for48 hr in basal medium (DMEM) and then treated with EGF (6 ng/well) or 50ul of the supernatants obtained in Example 30 for 5-20 minutes. Thecells are then solubilized and extracts filtered directly into the assayplate.

After incubation with the extract for 1 hr at RT, the wells are againrinsed. As a positive control, a commercial preparation of MAP kinase(10 ng/well) is used in place of A431 extract. Plates are then treatedwith a commercial polyclonal (rabbit) antibody (1 ug/ml) whichspecifically recognizes the phosphorylated epitope of the Erk-1 andErk-2 kinases (1 hr at RT). This antibody is biotinylated by standardprocedures. The bound polyclonal antibody is then quantitated bysuccessive incubations with Europium-streptavidin and Europiumfluorescence enhancing reagent in the Wallac DELFIA instrument(time-resolved fluorescence). An increased fluorescent signal overbackground indicates a phosphorylation by polypeptide of the presentinvention or a molecule induced by polypeptide of the present invention.

Example 40 Assay for the Stimulation of Bone Marrow CD34+CellProliferation

This assay is based on the ability of human CD34+ to proliferate in thepresence of hematopoietic growth factors and evaluates the ability ofisolated polypeptides expressed in mammalian cells to stimulateproliferation of CD34+cells.

It has been previously shown that most mature precursors will respond toonly a single signal. More immature precursors require at least twosignals to respond. Therefore, to test the effect of polypeptides onhematopoietic activity of a wide range of progenitor cells, the assaycontains a given polypeptide in the presence or absence of otherhematopoietic growth factors. Isolated cells are cultured for 5 days inthe presence of Stem Cell Factor (SCF) in combination with testedsample. SCF alone has a very limited effect on the proliferation of bonemarrow (BM) cells, acting in such conditions only as a “survival”factor. However, combined with any factor exhibiting stimulatory effecton these cells (e.g., IL-3), SCF will cause a synergistic effect.Therefore, if the tested polypeptide has a stimulatory effect onhematopoietic progenitors, such activity can be easily detected. Sincenormal BM cells have a low level of cycling cells, it is likely that anyinhibitory effect of a given polypeptide, or agonists or antagoniststhereof, might not be detected. Accordingly, assays for an inhibitoryeffect on progenitors is preferably tested in cells that are firstsubjected to in vitro stimulation with SCF+IL+3, and then contacted withthe compound that is being evaluated for inhibition of such inducedproliferation.

Briefly, CD34+cells are isolated using methods known in the art. Thecells are thawed and resuspended in medium (QBSF 60 serum-free mediumwith 1% L-glutamine (500 ml) Quality Biological, Inc., Gaithersburg, Md.Cat# 160-204-101). After several gentle centrifugation steps at 200×g,cells are allowed to rest for one hour. The cell count is adjusted to2.5×10⁵ cells/ml. During this time, 100 μl of sterile water is added tothe peripheral wells of a 96-well plate. The cytokines that can betested with a given polypeptide in this assay is rhSCF (R&D Systems,Minneapolis, Minn., Cat# 255-SC) at 50 ng/ml alone and in combinationwith rhSCF and rhIL-3 (R&D Systems, Minneapolis, Minn., Cat# 203-ML) at30 ng/ml. After one hour, 10 μl of prepared cytokines, 50 μl of thesupernatants prepared in Example 30 (supernatants at 1:2 dilution=50 μl)and 20 μl of diluted cells are added to the media which is alreadypresent in the wells to allow for a final total volume of 100 μl. Theplates are then placed in a 37° C./5% CO₂ incubator for five days.

Eighteen hours before the assay is harvested, 0.5 μCi/well of [3H]Thymidine is added in a 10 μl volume to each well to determine theproliferation rate. The experiment is terminated by harvesting the cellsfrom each 96-well plate to a filtermat using the Tomtec Harvester 96.After harvesting, the filtermats are dried, trimmed and placed intoOmniFilter assemblies consisting of one OmniFilter plate and oneOmniFilter Tray. 60 μL Microscint is added to each well and the platesealed with TopSeal-A press-on sealing film A bar code 15 sticker isaffixed to the first plate for counting. The sealed plates are thenloaded and the level of radioactivity determined via the Packard TopCount and the printed data collected for analysis. The level ofradioactivity reflects the amount of cell proliferation.

The studies described in this example test the activity of a givenpolypeptide to stimulate bone marrow CD34+cell proliferation. Oneskilled in the art could easily modify the exemplified studies to testthe activity of polynucleotides (e.g., gene therapy), antibodies,agonists, and/or antagonists and fragments and variants thereof. As anonlimiting example, potential antagonists tested in this assay would beexpected to inhibit cell proliferation in the presence of cytokinesand/or to increase the inhibition of cell proliferation in the presenceof cytokines and a given polypeptide. In contrast, potential agoniststested in this assay would be expected to enhance cell proliferationand/or to decrease the inhibition of cell proliferation in the presenceof cytokines and a given polypeptide.

The ability of a gene to stimulate the proliferation of bone marrowCD34+cells indicates that polynucleotides and polypeptides correspondingto the gene are useful for the diagnosis and treatment of disordersaffecting the immune system and hematopoiesis. Representative uses aredescribed in the “Immune Activity” and “Infectious Disease” sectionsabove, and elsewhere herein.

Example 41 Assay for Extracellular Matrix Enhanced Cell Response (EMECR)

The objective of the Extracellular Matrix Enhanced Cell Response (EMECR)assay is to identify gene products (e.g., isolated polypeptides) thatact on the hematopoietic stem cells in the context of the extracellularmatrix (ECM) induced signal.

Cells respond to the regulatory factors in the context of signal(s)received from the surrounding microenvironment. For example,fibroblasts, and endothelial and epithelial stem cells fail to replicatein the absence of signals from the ECM. Hematopoietic stem cells canundergo self-renewal in the bone marrow, but not in in vitro suspensionculture. The ability of stem cells to undergo self-renewal in vitro isdependent upon their interaction with the stromal cells and the ECMprotein fibronectin (fn). Adhesion of cells to fn is mediated by theα₅.β₁ and α₄.β₁ integrin receptors, which are expressed by human andmouse hematopoietic stem cells. The factor(s) which integrate with theECM environment and are responsible for stimulating stem cellself-renewal have a not yet been identified. Discovery of such factorsshould be of great interest in gene therapy and bone marrow transplantapplications

Briefly, polystyrene, non tissue culture treated, 96-well plates arecoated with fn fragment at a coating concentration of 0.2 μg/cm². Mousebone marrow cells are plated (1,000 cells/well) in 0.2 ml of serum-freemedium. Cells cultured in the presence of IL-3 (5 ng/ml)+SCF (50 ng/ml)would serve as the positive control, conditions under which littleself-renewal but pronounced differentiation of the stem cells is to beexpected. Gene products of the invention (e.g., including, but notlimited to, polynucleotides and polypeptides of the present invention,and supernatants produced in Example 30), are tested with appropriatenegative controls in the presence and absence of SCF (5.0 ng/ml), wheretest factor supernatants represent 10% of the total assay volume. Theplated cells are then allowed to grow by incubating in a low oxygenenvironment (5% CO₂, 7% O₂, and 88% N₂) tissue culture incubator for 7days. The number of proliferating cells within the wells is thenquantitated by measuring thymidine incorporation into cellular DNA.Verification of the positive hits in the assay will require phenotypiccharacterization of the cells, which can be accomplished by scaling upof the culture system and using appropriate antibody reagents againstcell surface antigens and FACScan.

One skilled in the art could easily modify the exemplified studies totest the activity of polynucleotides (e.g., gene therapy), antibodies,agonists, and/or antagonists and fragments and variants thereof.

If a particular polypeptide of the present invention is found to be astimulator of hematopoietic progenitors, polynucleotides andpolypeptides corresponding to the gene encoding said polypeptide may beuseful for the diagnosis and treatment of disorders affecting the immunesystem and hematopoiesis. Representative uses are described in the“Immune Activity” and “Infectious Disease” sections above, and elsewhereherein. The gene product may also be useful in the expansion of stemcells and committed progenitors of various blood lineages, and in thedifferentiation and/or proliferation of various cell types.

Additionally, the polynucleotides and/or polypeptides of the gene ofinterest and/or agonists and/or antagonists thereof, may also beemployed to inhibit the proliferation and differentiation ofhematopoietic cells and therefore may be employed to protect bone marrowstem cells from chemotherapeutic agents during chemotherapy. Thisantiproliferative effect may allow administration of higher doses ofchemotherapeutic agents and, therefore, more effective chemotherapeutictreatment.

Moreover, polynucleotides and polypeptides corresponding to the gene ofinterest may also be useful for the treatment and diagnosis ofhematopoietic related disorders such as, for example, anemia,pancytopenia, leukopenia, thrombocytopenia or leukemia since stromalcells are important in the production of cells of hematopoieticlineages. The uses include bone marrow cell ex-vivo culture, bone marrowtransplantation, bone marrow reconstitution, radiotherapy orchemotherapy of neoplasia.

Example 42 Human Dermal Fibroblast and Aortic Smooth Muscle CellProliferation

The polypeptide of interest is added to cultures of normal human dermalfibroblasts (NHDF) and human aortic smooth muscle cells (AoSMC) and twoco-assays are performed with each sample. The first assay examines theeffect of the polypeptide of interest on the proliferation of normalhuman dermal fibroblasts (NHDF) or aortic smooth muscle cells (AoSMC).Aberrant growth of fibroblasts or smooth muscle cells is a part ofseveral pathological processes, including fibrosis, and restenosis. Thesecond assay examines IL6 production by both NHDF and SMC. IL6production is an indication of functional activation. Activated cellswill have increased production of a number of cytokines and otherfactors, which can result in a proinflammatory or immunomodulatoryoutcome. Assays are run with and without co-TNFa stimulation, in orderto check for costimulatory or inhibitory activity.

Briefly, on day 1,96-well black plates are set up with 1000 cells/well(NHDF) or 2000 cells/well (AOSMC) in 100 μl culture media. NHDF culturemedia contains: Clonetics FB basal media, 1 mg/ml hFGF, 5 mg/ml insulin,50 mg/ml gentamycin, 2% FBS, while AoSMC culture media containsClonetics SM basal media, 0.5 μg/ml hEGF, 5 mg/ml insulin, 1 μg/ml hFGF,50 mg/ml gentamycin, 50 μg/ml Amphotericin B, 5% FBS. After incubationat 37° C. for at least 4-5 hours culture media is aspirated and replacedwith growth arrest media. Growth arrest media for NHDF containsfibroblast basal media, 50 mg/ml gentamycin, 2% FBS, while growth arrestmedia for AoSMC contains SM basal media, 50 mg/ml gentamycin, 50 μg/mlAmphotericin B, 0.4% FBS. Incubate at 37° C. until day 2.

On day 2, serial dilutions and templates of the polypeptide of interestare designed such that they always include media controls andknown-protein controls. For both stimulation and inhibition experiments,proteins are diluted in growth arrest media. For inhibition experiments,TNFa is added to a final concentration of 2 ng/ml (NHDF) or 5 ng/ml(AoSMC). Add 1/3 vol media containing controls or polypeptides of thepresent invention and incubate at 37 degrees C./5% CO₂ until day 5.

Transfer 60 μl from each well to another labeled 96-well plate, coverwith a plate-sealer, and store at 4 degrees C. until Day 6 (for IL6ELISA). To the remaining 100 μl in the cell culture plate, asepticallyadd Alamar Blue in an amount equal to 10% of the culture volume (10 μl).Return plates to incubator for 3 to 4 hours. Then measure fluorescencewith excitation at 530 nm and emission at 590 nm using the CytoFluor.This yields the growth stimulation/inhibition data.

On day 5, the IL6 ELISA is performed by coating a 96 well plate with50-100 ul/well of Anti-Human IL6 Monoclonal antibody diluted in PBS, pH7.4, incubate ON at room temperature.

On day 6, empty the plates into the sink and blot on paper towels.Prepare Assay Buffer containing PBS with 4% BSA. Block the plates with200 μl/well of Pierce Super Block blocking buffer in PBS for 1-2 hr andthen wash plates with wash buffer (PBS, 0.05% Tween-20). Blot plates onpaper towels. Then add 50 μl/well of diluted Anti-Human IL-6 Monoclonal,Biotin-labeled antibody at 0.50 mg/ml. Make dilutions of IL-6 stock inmedia (30, 10, 3, 1, 0.3, 0 ng/ml). Add duplicate samples to top row ofplate. Cover the plates and incubate for 2 hours at RT on shaker.

Plates are washed with wash buffer and blotted on paper towels. DiluteEU-labeled Streptavidin 1:1000 in Assay buffer, and add 100 μl/well.Cover the plate and incubate 1 h at RT. Plates are again washed withwash buffer and blotted on paper towels.

Add 100 μl/well of Enhancement Solution. Shake for 5 minutes. Read theplate on the Wallac DELFIA Fluorometer. Readings from triplicate samplesin each assay were tabulated and averaged.

A positive result in this assay suggests AoSMC cell proliferation andthat the polypeptide of the present invention may be involved in dermalfibroblast proliferation and/or smooth muscle cell proliferation. Apositive result also suggests many potential uses of polypeptides,polynucleotides, agonists and/or antagonists of thepolynucleotide/polypeptide of the present invention which gives apositive result. For example, inflammation and immune responses, woundhealing, and angiogenesis, as detailed throughout this specification.Particularly, polypeptides of the present invention and polynucleotidesof the present invention may be used in wound healing and dermalregeneration, as well as the promotion of vasculogenesis, both of theblood vessels and lymphatics. The growth of vessels can be used in thetreatment of, for example, cardiovascular diseases. Additionally,antagonists of polypeptides and polynucleotides of the invention may beuseful in treating diseases, disorders, and/or conditions which involveangiogenesis by acting as an anti-vascular agent (e.g.,anti-angiogenesis). These diseases, disorders, and/or conditions areknown in the art and/or are described herein, such as, for example,malignancies, solid tumors, benign tumors, for example hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, for example,diabetic retinopathy, retinopathy of prematurity, macular degeneration,corneal graft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, uvietis and Pterygia (abnormal blood vesselgrowth) of the eye; rheumatoid arthritis; psoriasis; delayed woundhealing; endometriosis; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; myocardial angiogenesis; coronary collaterals; cerebralcollaterals; arteriovenous malformations; ischemic limb angiogenesis;Osler-Webber Syndrome; plaque neovascularization; telangiectasia;hemophiliac joints; angiofibroma; fibromuscular dysplasia; woundgranulation; Crohn's disease; and atherosclerosis. Moreover, antagonistsof polypeptides and polynucleotides of the invention may be useful intreating anti-hyperproliferative diseases and/or anti-inflammatory knownin the art and/or described herein.

One skilled in the art could easily modify the exemplified studies totest the activity of polynucleotides (e.g., gene therapy), antibodies,agonists, and/or antagonists and fragments and variants thereof.

Example 43 Cellular Adhesion Molecule (CAM) Expression on EndothelialCells

The recruitment of lymphocytes to areas of inflammation and angiogenesisinvolves specific receptor-ligand interactions between cell surfaceadhesion molecules (CAMs) on lymphocytes and the vascular endothelium.The adhesion process, in both normal and pathological settings, followsa multi-step cascade that involves intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelialleukocyte adhesion molecule-1 (E-selectin) expression on endothelialcells (EC). The expression of these molecules and others on the vascularendothelium determines the efficiency with which leukocytes may adhereto the local vasculature and extravasate into the local tissue duringthe development of an inflammatory response. The local concentration ofcytokines and growth factor participate in the modulation of theexpression of these CAMs.

Briefly, endothelial cells (e.g., Human Umbilical Vein Endothelial cells(HUVECs)) are grown in a standard 96 well plate to confluence, growthmedium is removed from the cells and replaced with 100 μl of 199 Medium(10% fetal bovine serum (FBS)). Samples for testing and positive ornegative controls are added to the plate in triplicate (in 10 μlvolumes). Plates are then incubated at 37° C. for either 5 h (selectinand integrin expression) or 24 h (integrin expression only). Plates areaspirated to remove medium and 100 μl of 0.1% paraformaldehyde-PBS (withCa++ and Mg++) is added to each well. Plates are held at 4° C. for 30min. Fixative is removed from the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained. 10 μl of diluted primary antibody isadded to the test and control wells. Anti-ICAM-1-Biotin,Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at aconcentration of 10 μg/ml (1:10 dilution of 0.1 mg/ml stock antibody).Cells are incubated at 37° C. for 30 min. in a humidified environment.Wells are washed three times with PBS (+Ca,Mg)+0.5% BSA. 20 μl ofdiluted ExtrAvidin-Alkaline Phosphatase (1:5,000 dilution, referred toherein as the working dilution) are added to each well and incubated at37° C. for 30 min. Wells are washed three times with PBS (+Ca,Mg)+0.5%BSA. Dissolve 1 tablet of p-Nitrophenol Phosphate pNPP per 5 ml ofglycine buffer (pH 10.4). 100 μl of pNPP substrate in glycine buffer isadded to each test well. Standard wells in triplicate are prepared fromthe working dilution of the ExtrAvidin-Alkaline Phosphotase in glycinebuffer: 1:5,000 (10⁰)>10^(−0.5)>10⁻¹>10^(1.5)0.5 μl of each dilution isadded to triplicate wells and the resulting AP content in each well is5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent is then addedto each of the standard wells. The plate is incubated at 37° C. for 4 h.A volume of 50 μl of 3M NaOH is added to all wells. The plate is read ona plate reader at 405 nm using the background subtraction option onblank wells filled with glycine buffer only. Additionally, the templateis set up to indicate the concentration of AP-conjugate in each standardwell [5.50 ng; 1.74 ng; 0.55 ng; 0.18 ng]. Results are indicated asamount of bound AP-conjugate in each sample.

Example 44 Alamar Blue Endothelial Cells Proliferation Assay

This assay may be used to quantitatively determine protein mediatedinhibition of bFGF-induced proliferation of Bovine Lymphatic EndothelialCells (LECs), Bovine Aortic Endothelial Cells (BAECs) or HumanMicrovascular Uterine Myometrial Cells (UTMECs). This assay incorporatesa fluorometric growth indicator based on detection of metabolicactivity. A standard Alamar Blue Proliferation Assay is prepared inEGM-2MV with 10 ng/ml of bFGF added as a source of endothelial cellstimulation. This assay may be used with a variety of endothelial cellswith slight changes in growth medium and cell concentration. Dilutionsof the protein batches to be tested are diluted as appropriate.Serum-free medium (GIBCO SFM) without bFGF is used as a non-stimulatedcontrol and Angiostatin or TSP-1 are included as a known inhibitorycontrols.

Briefly, LEC, BAECs or UTMECs are seeded in growth media at a density of5000 to 2000 cells/well in a 96 well plate and placed at 37 degreesCovernight. After the overnight incubation of the cells, the growth mediais removed and replaced with GIBCO EC-SFM. The cells are treated withthe appropriate dilutions of the protein of interest or control proteinsample(s) (prepared in SFM) in triplicate wells with additional bFGF toa concentration of 10 ng/ml. Once the cells have been treated with thesamples, the plate(s) is/are placed back in the 37° C. incubator forthree days. After three days 10 ml of stock alamar blue (Biosource Cat#DAL100) is added to each well and the plate(s) is/are placed back in the37° C. incubator for four hours. The plate(s) are then read at 530 nmexcitation and 590 nm emission using the CytoFluor fluorescence reader.Direct output is recorded in relative fluorescence units.

Alamar blue is an oxidation-reduction indicator that both fluoresces andchanges color in response to chemical reduction of growth mediumresulting from cell growth. As cells grow in culture, innate metabolicactivity results in a chemical reduction of the immediate surroundingenvironment. Reduction related to growth causes the indicator to changefrom oxidized (non-fluorescent blue) form to reduced (fluorescent red)form (i.e., stimulated proliferation will produce a stronger signal andinhibited proliferation will produce a weaker signal and the totalsignal is proportional to the total number of cells as well as theirmetabolic activity). The background level of activity is observed withthe starvation medium alone. This is compared to the output observedfrom the positive control samples (bFGF in growth medium) and proteindilutions.

Example 45 Detection of Inhibition of a Mixed Lymphocyte Reaction

This assay can be used to detect and evaluate inhibition of a MixedLymphocyte Reaction (MLR) by gene products (e.g., isolatedpolypeptides). Inhibition of a MLR may be due to a direct effect on cellproliferation and viability, modulation of costimulatory molecules oninteracting cells, modulation of adhesiveness between lymphocytes andaccessory cells, or modulation of cytokine production by accessorycells. Multiple cells may be targeted by these polypeptides since theperipheral blood mononuclear fraction used in this assay includes T, Band natural killer lymphocytes, as well as monocytes and dendriticcells.

Polypeptides of interest found to inhibit the MLR may find applicationin diseases associated with lymphocyte and monocyte activation orproliferation. These include, but are not limited to, diseases such asasthma, arthritis, diabetes, inflammatory skin conditions, psoriasis,eczema, systemic lupus erythematosus, multiple sclerosis,glomerulonephritis, inflammatory bowel disease, crohn's disease,ulcerative colitis, arteriosclerosis, cirrhosis, graft vs. host disease,host vs. graft disease, hepatitis, leukemia and lymphoma.

Briefly, PBMCs from human donors are purified by density gradientcentrifugation using Lymphocyte Separation Medium (LSM®, density 1.0770g/ml, Organon Teknika Corporation, West Chester, Pa.). PBMCs from twodonors are adjusted to 2×10⁶ cells/ml in RPMI-1640 (Life Technologies,Grand Island, N.Y.) supplemented with 10% FCS and 2 mM glutamine. PBMCsfrom a third donor is adjusted to 2×10⁵ cells/ml. Fifty microliters ofPBMCs from each donor is added to wells of a 96-well round bottommicrotiter plate. Dilutions of test materials (50 μl) is added intriplicate to microtiter wells. Test samples (of the protein ofinterest) are added for final dilution of 1:4; rhuIL-2 (R&D Systems,Minneapolis, Minn., catalog number 202-IL) is added to a finalconcentration of 1 μg/ml; anti-CD4 mAb (R&D Systems, clone 34930.11,catalog number MAB379) is added to a final concentration of 10 μg/ml.Cells are cultured for 7-8 days at 37° C. in 5% CO₂, and 1 μC of [³H]thymidine is added to wells for the last 16 hrs of culture. Cells areharvested and thymidine incorporation determined using a PackardTopCount. Data is expressed as the mean and standard deviation oftriplicate determinations.

Samples of the protein of interest are screened in separate experimentsand compared to the negative control treatment, anti-CD4 mAb, whichinhibits proliferation of lymphocytes and the positive controltreatment, IL-2 (either as recombinant material or supernatant), whichenhances proliferation of lymphocytes.

One skilled in the art could easily modify the exemplified studies totest the activity of polynucleotides (e.g., gene therapy), antibodies,agonists, and/or antagonists and fragments and variants thereof.

Example 46 Assays for Protease Activity

The following assay may be used to assess protease activity of thepolypeptides of the invention.

Gelatin and casein zymography are performed essentially as described(Heusen et al., Anal. Biochem., 102:196-202 (1980); Wilson et al.,Journal of Urology, 149:653-658 (1993)). Samples are run on 10%polyacryamide/0.1% SDS gels containing 1% gelain orcasein, soaked in2.5% triton at room temperature for 1 hour, and in 0.1M glycine, pH 8.3at 37° C. 5 to 16 hours. After staining in amido black areas ofproteolysis apear as clear areas agains the blue-black background.Trypsin (Sigma T8642) is used as a positive control.

Protease activity is also determined by monitoring the cleavage ofn-a-benzoyl-L-arginine ethyl ester (BAEE) (Sigma B-4500. Reactions areset up in (25 mMNaPO₄, 1 mM EDTA, and 1 mM BAEE), pH 7.5. Samples areadded and the change in adsorbance at 260 nm is monitored on the BeckmanDU-6 spectrophotometer in the time-drive mode. Trypsin is used as apositive control.

Additional assays based upon the release of acid-soluble peptides fromcasein or hemoglobin measured as adsorbance at 280 nm orcolorimetrically using the Folin method are performed as described inBergmeyer, et al., Methods of Enzymatic Analysis, 5 (1984). Other assaysinvolve the solubilization of chromogenic substrates (Ward, AppliedScience, 251-317 (1983)).

Example 47 Identifying Serine Protease Substrate Specificity

Methods known in the art or described herein may be used to determinethe substrate specificity of the polypeptides of the present inventionhaving serine protease activity. A preferred method of determiningsubstrate specificity is by the use of positional scanning syntheticcombinatorial libraries as described in GB 2 324 529 (incorporatedherein in its entirety).

Example 48 Ligand Binding Assays

The following assay may be used to assess ligand binding activity of thepolypeptides of the invention.

Ligand binding assays provide a direct method for ascertaining receptorpharmacology and are adaptable to a high throughput format. The purifiedligand for a polypeptide is radiolabeled to high specific activity(50-2000 Ci/mmol) for binding studies. A determination is then made thatthe process of radiolabeling does not diminish the activity of theligand towards its polypeptide. Assay conditions for buffers, ions, pHand other modulators such as nucleotides are optimized to establish aworkable signal to noise ratio for both membrane and whole cellpolypeptide sources. For these assays, specific polypeptide binding isdefined as total associated radioactivity minus the radioactivitymeasured in the presence of an excess of unlabeled competing ligand.Where possible, more than one competing ligand is used to defineresidual nonspecific binding.

Example 49 Functional Assay in Xenopus Oocytes

Capped RNA transcripts from linearized plasmid templates encoding thepolypeptides of the invention are synthesized in vitro with RNApolymerases in accordance with standard procedures. In vitro transcriptsare suspended in water at a final concentration of 0.2 mg/ml. Ovarianlobes are removed from adult female toads, Stage V defolliculatedoocytes are obtained, and RNA transcripts (10 ng/oocytc) are injected ina 50 nl bolus using a microinjection apparatus. Two electrode voltageclamps are used to measure the currents from individual Xenopus oocytesin response polypeptides and polypeptide agonist exposure. Recordingsare made in Ca2+ free Barth's medium at room temperature. The Xenopussystem can be used to screen known ligands and tissue/cell extracts foractivating ligands.

Example 50 Microphysiometric Assays

Activation of a wide variety of secondary messenger systems results inextrusion of small amounts of acid from a cell. The acid formed islargely as a result of the increased metabolic activity required to fuelthe intracellular signaling process. The pH changes in the mediasurrounding the cell are very small but are detectable by the CYTOSENSORmicrophysiometer (Molecular Devices Ltd., Menlo Park, Calif.). TheCYTOSENSOR is thus capable of detecting the activation of polypeptidewhich is coupled to an energy utilizing intracellular signaling pathway.

Example 51 Extract/Cell Supernatant Screening

A large number of mammalian receptors exist for which there remains, asyet, no cognate activating ligand (agonist). Thus, active ligands forthese receptors may not be included within the ligands banks asidentified to date. Accordingly, the polypeptides of the invention canalso be functionally screened (using calcium, cAMP, microphysiometer,oocyte electrophysiology, etc., functional screens) against tissueextracts to identify its natural ligands. Extracts that produce positivefunctional responses can be sequentially subfractionated until anactivating ligand is isolated and identified.

Example 52 Calcium and cAMP Functional Assays

Seven transmembrane receptors which are expressed in HEK 293 cells havebeen shown to be coupled functionally to activation of PLC and calciummobilization and/or cAMP stimulation or inhibition. Basal calcium levelsin the HEK 293 cells in receptor-transfected or vector control cellswere observed to be in the normal, 100 nM to 200 nM, range. HEK 293cells expressing recombinant receptors are loaded with fura 2 and in asingle day >150 selected ligands or tissue/cell extracts are evaluatedfor agonist induced calcium mobilization. Similarly, HEK 293 cellsexpressing recombinant receptors are evaluated for the stimulation orinhibition of cAMP production using standard cAMP quantitation assays.Agonists presenting a calcium transient or cAMP fluctuation are testedin vector control cells to determine if the response is unique to thetransfected cells expressing receptor.

Example 53 ATP-Binding Assay

The following assay may be used to assess ATP-binding activity ofpolypeptides of the invention.

ATP-binding activity of the polypeptides of the invention may bedetected using the ATP-binding assay described in U.S. Pat. No.5,858,719, which is herein incorporated by reference in its entirety.Briefly, ATP-binding to polypeptides of the invention is measured viaphotoaffinity labeling with 8-azido-ATP in a competition assay. Reactionmixtures containing 1 mg/ml of the ABC transport protein of the presentinvention are incubated with varying concentrations of ATP, or thenon-hydrolyzable ATP analog adenyl-5′-imidodiphosphate for 10 minutes at4° C. A mixture of 8-azido-ATP (Sigma Chem. Corp., St. Louis, Mo.) plus8-azido-ATP (³²P-ATP) (5 mCi/μmol, ICN, Irvine Calif.) is added to afinal concentration of 100 μM and 0.5 ml aliquots are placed in thewells of a porcelain spot plate on ice. The plate is irradiated using ashort wave 254 nm UV lamp at a distance of 2.5 cm from the plate for twoone-minute intervals with a one-minute cooling interval in between. Thereaction is stopped by addition of dithiothreitol to a finalconcentration of 2 mM. The incubations are subjected to SDS-PAGEelectrophoresis, dried, and autoradiographed. Protein bandscorresponding to the particular polypeptides of the invention areexcised, and the radioactivity quantified. A decrease in radioactivitywith increasing ATP or adenly-5′-imidodiphosphate provides a measure ofATP affinity to the polypeptides.

Example 54 Small Molecule Screening

This invention is particularly useful for screening therapeuticcompounds by using the polypeptides of the invention, or bindingfragments thereof, in any of a variety of drug screening techniques. Thepolypeptide or fragment employed in such a test may be affixed to asolid support, expressed on a cell surface, free in solution, or locatedintracellularly. One method of drug screening utilizes eukaryotic orprokaryotic host cells which are stably transformed with recombinantnucleic acids expressing the polypeptide or fragment. Drugs are screenedagainst such transformed cells in competitive binding assays. One maymeasure, for example, the formulation of complexes between the agentbeing tested and polypeptide of the invention.

Thus, the present invention provides methods of screening for drugs orany other agents which affect activities mediated by the polypeptides ofthe invention. These methods comprise contacting such an agent with apolypeptide of the invention or fragment thereof and assaying for thepresence of a complex between the agent and the polypeptide or fragmentthereof, by methods well known in the art. In such a competitive bindingassay, the agents to screen are typically labeled. Following incubation,free agent is separated from that present in bound form, and the amountof free or uncomplexed label is a measure of the ability of a particularagent to bind to the polypeptides of the invention.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to the polypeptides ofthe invention, and is described in great detail in European PatentApplication 84/03564, published on Sep. 13, 1984, which is hereinincorporated by reference in its entirety. Briefly stated, large numbersof different small molecule test compounds are synthesized on a solidsubstrate, such as plastic pins or some other surface. The testcompounds are reacted with polypeptides of the invention and washed.Bound polypeptides are then detected by methods well known in the art.Purified polypeptides are coated directly onto plates for use in theaforementioned drug screening techniques. In addition, non-neutralizingantibodies may be used to capture the peptide and immobilize it on thesolid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding polypeptidesof the invention specifically compete with a test compound for bindingto the polypeptides or fragments thereof. In this manner, the antibodiesare used to detect the presence of any peptide which shares one or moreantigenic epitopes with a polypeptide of the invention.

Example 55 Phosphorylation Assay

In order to assay for phosphorylation activity of the polypeptides ofthe invention, a phosphorylation assay as described in U.S. Pat. No.5,958,405 (which is herein incorporated by reference) is utilized.Briefly, phosphorylation activity may be measured by phosphorylation ofa protein substrate using gamma-labeled ³²P-ATP and quantitation of theincorporated radioactivity using a gamma radioisotope counter. Thepolypeptides of the invention are incubated with the protein substrate,³²P-ATP, and a kinase buffer. The ³²P incorporated into the substrate isthen separated from free ³²P-ATP by electrophoresis, and theincorporated ³²P is counted and compared to a negative control.Radioactivity counts above the negative control are indicative ofphosphorylation activity of the polypeptides of the invention.

Example 56 Detection of Phosphorylation Activity (Activation) of thePolypeptides of the Invention in the Presence of Polypeptide Ligands

Methods known in the art or described herein may be used to determinethe phosphorylation activity of the polypeptides of the invention. Apreferred method of determining phosphorylation activity is by the useof the tyrosine phosphorylation assay as described in U.S. Pat. No.5,817,471 (incorporated herein by reference).

Example 57 Identification of Signal Transduction Proteins that Interactwith Polypeptides of the Present Invention

The purified polypeptides of the invention are research tools for theidentification, characterization and purification of additional signaltransduction pathway proteins or receptor proteins. Briefly, labeledpolypeptides of the invention are useful as reagents for thepurification of molecules with which it interacts. In one embodiment ofaffinity purification, polypeptides of the invention are covalentlycoupled to a chromatography column. Cell-free extract derived fromputative target cells, such as carcinoma tissues, is passed over thecolumn, and molecules with appropriate affinity bind to the polypeptidesof the invention. The protein complex is recovered from the column,dissociated, and the recovered molecule subjected to N-terminal proteinsequencing. This amino acid sequence is then used to identify thecaptured molecule or to design degenerate oligonucleotide probes forcloning the relevant gene from an appropriate cDNA library.

Example 58 IL-6 Bioassay

To test the proliferative effects of the polypeptides of the invention,the IL-6 Bioassay as described by Marz et al. is utilized (Proc. Natl.Acad. Sci., U.S.A., 95:3251-56 (1998), which is herein incorporated byreference). Briefly, IL-6 dependent B9 murine cells are washed threetimes in IL-6 free medium and plated at a concentration of 5,000 cellsper well in 50 μl, and 50 μl of the IL-6-like polypeptide is added.After 68 hrs. at 37° C., the number of viable cells is measured byadding the tetrazolium salt thiazolyl blue (MTT) and incubating for afurther 4 hrs. at 37° C. B9 cells are lysed by SDS and optical densityis measured at 570 nm. Controls containing IL-6 (positive) and nocytokine (negative) are utilized. Enhanced proliferation in the testsample(s) relative to the negative control is indicative ofproliferative effects mediated by polypeptides of the invention.

Example 59 Support of Chicken Embryo Neuron Survival

To test whether sympathetic neuronal cell viability is supported bypolypeptides of the invention, the chicken embryo neuronal survivalassay of Senaldi et al is utilized (Proc. Natl. Acad. Sci., U.S.A.,96:11458-63 (1998), which is herein incorporated by reference). Briefly,motor and sympathetic neurons are isolated from chicken embryos,resuspended in L15 medium (with 10% FCS, glucose, sodium selenite,progesterone, conalbumin, putrescine, and insulin; Life Technologies,Rockville, Md.) and Dulbecco's modified Eagles medium [with 10% FCS,glutamine, penicillin, and 25 mM Hepes buffer (pH 7.2); LifeTechnologies, Rockville, Md.], respectively, and incubated at 37° C. in5% CO₂ in the presence of different concentrations of the purifiedIL-6-like polypeptide, as well as a negative control lacking anycytokine. After 3 days, neuron survival is determined by evaluation ofcellular morphology, and through the use of the calorimetric assay ofMosmann (Mosmann, T., J. Immunol. Methods, 65:55-63 (1983)). Enhancedneuronal cell viability as compared to the controls lacking cytokine isindicative of the ability of the inventive purified IL-6-likepolypeptide(s) to enhance the survival of neuronal cells.

Example 60 Assay for Phosphatase Activity

The following assay may be used to assess serine/threonine phosphatase(PTPase) activity of the polypeptides of the invention.

In order to assay for serine/threonine phosphatase (PTPase) activity,assays can be utilized which are widely known to those skilled in theart. For example, the serine/threonine phosphatase (PSPase) activity ismeasured using a PSPase assay kit from New England Biolabs, Inc. Myelinbasic protein (MyBP), a substrate for PSPase, is phosphorylated onserine and threonine residues with cAMP-dependent Protein Kinase in thepresence of [³²P]ATP. Protein serine/threonine phosphatase activity isthen determined by measuring the release of inorganic phosphate from³²P-labeled MyBP.

Example 61 Interaction of Serine/Threonine Phosphatases with otherProteins

The polypeptides of the invention with serine/threonine phosphataseactivity as determined in Example 60 are research tools for theidentification, characterization and purification of additionalinteracting proteins or receptor proteins, or other signal transductionpathway proteins. Briefly, labeled polypeptide(s) of the invention isuseful as a reagent for the purification of molecules with which itinteracts. In one embodiment of affinity purification, polypeptide ofthe invention is covalently coupled to a chromatography column.Cell-free extract derived from putative target cells, such as neural orliver cells, is passed over the column, and molecules with appropriateaffinity bind to the polypeptides of the invention. The polypeptides ofthe invention-complex is recovered from the column, dissociated, and therecovered molecule subjected to N-terminal protein sequencing. Thisamino acid sequence is then used to identify the captured molecule or todesign degenerate oligonucleotide probes for cloning the relevant genefrom an appropriate cDNA library.

Example 62 Assaying for Heparanase Activity

In order to assay for heparanase activity of the polypeptides of theinvention, the heparanase assay described by Vlodavsky et al is utilized(Vlodavsky, I., et al., Nat. Med., 5:793-802 (1999)). Briefly, celllysates, conditioned media or intact cells (1×10⁶ cells per 35-mm dish)are incubated for 18 hrs at 37° C., pH 6.2-6.6, with ³⁵S-labeled ECM orsoluble ECM derived peak I proteoglycans. The incubation medium iscentrifuged and the supernatant is analyzed by gel filtration on aSepharose CL-6B column (0.9×30 cm). Fractions are eluted with PBS andtheir radioactivity is measured. Degradation fragments of heparansulfate side chains are eluted from Sepharose 6B at 0.5<K_(av)<0.8 (peakII). Each experiment is done at least three times. Degradation fragmentscorresponding to “peak II,” as described by Vlodavsky et al., isindicative of the activity of the polypeptides of the invention incleaving heparan sulfate.

Example 63 Immobilization of Biomolecules

This example provides a method for the stabilization of polypeptides ofthe invention in non-host cell lipid bilayer constucts (see, e.g., Bieriet al., Nature Biotech 17:1105-1108 (1999), hereby incorporated byreference in its entirety herein) which can be adapted for the study ofpolypeptides of the invention in the various functional assays describedabove. Briefly, carbohydrate-specific chemistry for biotinylation isused to confine a biotin tag to the extracellular domain of thepolypeptides of the invention, thus allowing uniform orientation uponimmobilization. A 50 uM solution of polypeptides of the invention inwashed membranes is incubated with 20 mM NaIO4 and 1.5 mg/ml (4 mM) BACHor 2 mg/ml (7.5 mM) biotin-hydrazide for 1 hr at room temperature(reaction volume, 150 ul). Then the sample is dialyzed (PierceSlidealizer Cassett, 10 kDa cutoff; Pierce Chemical Co., Rockford Ill.)at 4C first for 5 h, exchanging the buffer after each hour, and finallyfor 12 h against 500 ml buffer R (0.15 M NaCl, 1 mM MgCl2, 10 mM sodiumphosphate, pH7). Just before addition into a cuvette, the sample isdiluted 1:5 in buffer ROG50 (Buffer R supplemented with 50 mMoctylglucoside).

Example 64 TAQMAN

Quantitative PCR (QPCR). Total RNA from cells in culture are extractedby Trizol separation as recommended by the supplier (LifeTechnologies).(Total RNA is treated with DNase I (Life Technologies) to remove anycontaminating genomic DNA before reverse transcription.) Total RNA (50ng) is used in a one-step, 50 ul, RT-QPCR, consisting of Taqman Buffer A(Perkin-Elmer; 50 mM KCl/10 mM Tris, pH 8.3), 5.5 mM MgCl₂, 240 μM eachdNTP, 0.4 units RNase inhibitor (Promega), 8% glycerol, 0.012% Tween-20,0.05% gelatin, 0.3 uM primers, 0.1 uM probe, 0.025 units Amplitaq Gold(Perkin-Elmer) and 2.5 units Superscript II reverse transcriptase (LifeTechnologies). As a control for genomic contamination, parallelreactions are setup without reverse transcriptase. The relativeabundance of (unknown) and 18S RNAs are assessed by using the AppliedBiosystems Prism 7700 Sequence Detection System (Livak, K. J., Flood, S.J., Marmaro, J., Giusti, W. & Deetz, K. (1995) PCR Methods Appl. 4,357-362). Reactions are carried out at 48° C. for 30 min, 95° C. for 10min, followed by 40 cycles of 95° C. for 15 s, 60° C. for 1 min.Reactions are performed in triplicate.

Primers (f & r) and FRET probes sets are designed using Primer ExpressSoftware (Perkin-Elmer). Probes are labeled at the 5′-end with thereporter dye 6-FAM and on the 3′-end with the quencher dye TAMRA(Biosource International, Camarillo, Calif. or Perkin-Elmer).

Example 65 Assays for Metalloproteinase Activity

Metalloproteinases (EC 3.4.24.-) are peptide hydrolases which use metalions, such as Zn²⁺, as the catalytic mechanism. Metalloproteinaseactivity of polypeptides of the present invention can be assayedaccording to the following methods.

Proteolysis of Alpha-2-Macroglobulin

To confirm protease activity, purified polypeptides of the invention aremixed with the substrate alpha-2-macroglobulin (0.2 unit/ml; BoehringerMannheim, Germany) in 1× assay buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl,10 mM CaCl₂, 25 μM ZnCl₂ and 0.05% Brij-35) and incubated at 37° C. for1-5 days. Trypsin is used as positive control. Negative controls containonly alpha-2-macroglobulin in assay buffer. The samples are collectedand boiled in SDS-PAGE sample buffer containing 5% 2-mercaptoethanol for5-min, then loaded onto 8% SDS-polyacrylamide gel. After electrophoresisthe proteins are visualized by silver staining. Proteolysis is evidentby the appearance of lower molecular weight bands as compared to thenegative control.

Inhibition of Alpha-2-Macroglobulin Proteolysis by Inhibitors ofMetalloproteinases

Known metalloproteinase inhibitors (metal chelators (EDTA, EGTA, ANDHgCl₂), peptide metalloproteinase inhibitors (TIMP-1 and TIMP-2), andcommercial small molecule MMP inhibitors) are used to characterize theproteolytic activity of polypeptides of the invention. The threesynthetic MMP inhibitors used are: MMP inhibitor I, [IC₅₀=1.0 μM againstMMP-1 and MMP-8; IC₅₀=30 μM against MMP-9; IC₅₀=150 μM against MMP-3];MMP-3 (stromelysin-1) inhibitor I [IC₅₀=5 μM against MMP-3], and MMP-3inhibitor II [K_(i)=130 nM against MMP-3]; inhibitors available throughCalbiochem, catalog # 444250, 444218, and 444225, respectively).Briefly, different concentrations of the small molecule MMP inhibitorsare mixed with purified polypeptides of the invention (50 μg/ml) in 22.9μl of 1× HEPES buffer (50 mM HEPES, pH 7.5, 0.2 M NaCl, 10 mM CaCl₂, 25μM ZnCl₂ and 0.05% Brij-35) and incubated at room temperature (24° C.)for 2-hr, then 7.1 μl of substrate alpha-2-macroglobulin (0.2 unit/ml)is added and incubated at 37° C. for 20-hr. The reactions are stopped byadding 4× sample buffer and boiled immediately for 5 minutes. AfterSDS-PAGE, the protein bands are visualized by silver stain.

Synthetic Fluorogenic Peptide Substrates Cleavage Assay

The substrate specificity for polypeptides of the invention withdemonstrated metalloproteinase activity can be determined usingsynthetic fluorogenic peptide substrates (purchased from BACHEMBioscience Inc). Test substrates include, M-1985, M-2225, M-2105,M-2110, and M-2255. The first four are MMP substrates and the last oneis a substrate of tumor necrosis factor-α (TNF-α) converting enzyme(TACE). All the substrates are prepared in 1:1 dimethyl sulfoxide (DMSO)and water. The stock solutions are 50-500 μM. Fluorescent assays areperformed by using a Perkin Elmer LS 50B luminescence spectrometerequipped with a constant temperature water bath. The excitation λ is 328nm and the emission λ is 393 nm. Briefly, the assay is carried out byincubating 176 μl 1× HEPES buffer (0.2 M NaCl, 10 mM CaCl₂, 0.05%Brij-35 and 50 mM HEPES, pH 7.5) with 4 μl of substrate solution (50 μM)at 25° C. for 15 minutes, and then adding 20 μl of a purifiedpolypeptide of the invention into the assay cuvett. The finalconcentration of substrate is 1 μM. Initial hydrolysis rates aremonitored for 30-min.

Example 66 Characterization of the cDNA Contained in a Deposited Plasmid

The size of the cDNA insert contained in a deposited plasmid may beroutinely determined using techniques known in the art, such as PCRamplification using synthetic primers hybridizable to the 3′ and 5′ endsof the cDNA sequence. For example, two primers of 17-30 nucleotidesderived from each end of the cDNA (i.e., hybridizable to the absolute 5′nucleotide or the 3′ nucleotide end of the sequence of SEQ ID NO:X,respectively) are synthesized and used to amplify the cDNA using thedeposited cDNA plasmid as a template. The polymerase chain reaction iscarried out under routine conditions, for instance, in 25 ul of reactionmixture with 0.5 ug of the above cDNA template. A convenient reactionmixture is 1.5-5 mM MgCl₂, 0.01% (w/v) gelatin, 20 uM each of dATP,dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taqpolymerase. Thirty five cycles of PCR (denaturation at 94 degree C. for1 min; annealing at 55 degree C. for 1 min; elongation at 72 degree C.for 1 min) are performed with a Perkin-Elmer Cetus automated thermalcycler. The amplified product is analyzed by agarose gelelectrophoresis. The PCR product is verified to be the selected sequenceby subcloning and sequencing the DNA product. It will be clear that theinvention may be practiced otherwise than as particularly described inthe foregoing description and examples. Numerous modifications andvariations of the present invention are possible in light of the aboveteachings and, therefore, are within the scope of the appended claims.

INCORPORATION BY REFERENCE

The entire disclosure of each document cited (including patents, patentapplications, journal articles, abstracts, laboratory manuals, books, orother disclosures) in the Background of the Invention, DetailedDescription, and Examples is hereby incorporated herein by reference. Inaddition, the sequence listing submitted herewith is incorporated hereinby reference in its entirety. The specification and sequence listing ofeach of the following U.S. and PCT applications are herein incorporatedby reference in their entirety (filing dates shown in format“year-month-day” (yyyy-mm-dd)): Application No. 60/278,650 filed on2001-03-27, application Ser. No. 09/950,082 filed on 2001-09-12,application Ser. No. 09/950,083 filed on 2001-09-12, Application No.60/306,171 filed on 19 Jul. 2001, application Ser. 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No.PCT/US00/07722 filed on 2000-03-23, Application No. PCT/US00/07578 filedon 2000-03-23, Application No. PCT/US00/07726 filed on 2000-03-23,Application No. PCT/US00/07677 filed on 2000-03-23, Application No.PCT/US00/07725 filed on 2000-03-23, Application No. PCT/US00/09070 filedon 2000-04-06, Application No. PCT/US00/08982 filed on 2000-04-06,Application No. PCT/US00/08983 filed on 2000-04-06, Application No.PCT/US00/09067 filed on 2000-04-06, Application No. PCT/US00/09066 filedon 2000-04-06, Application No. PCT/US00/09068 filed on 2000-04-06,Application No. PCT/US00/08981 filed on 2000-04-06, Application No.PCT/US00/08980 filed on 2000-04-06, Application No. PCT/US00/09071 filedon 2000-04-06, Application No. PCT/US00/09069 filed on 2000-04-06,Application No. PCT/US00/15136 filed on 2000-06-01, Application No.PCT/US00/14926 filed on 2000-06-01, Application No. PCT/US00/14963 filedon 2000-06-01, Application No. PCT/US00/15135 filed on 2000-06-01,Application No. PCT/US00/14934 filed on 2000-06-01, Application No.PCT/US00/14933 filed on 2000-06-01, Application No. PCT/US00/15137 filedon 2000-06-01, Application No. PCT/US00/14928 filed on 2000-06-01,Application No. PCT/US00/14973 filed on 2000-06-01, Application No.PCT/US00/14964 filed on 2000-06-01, Application No. PCT/US00/26376 filedon 2000-09-26, Application No. PCT/US00/26371 filed on 2000-09-26,Application No. PCT/US00/26324 filed on 2000-09-26, Application No.PCT/US00/26323 filed on 2000-09-26, Application No. PCT/US00/26337 filedon 2000-09-26, Application No. PCT/US01/13318 filed on 2001-04-27,Application No. U.S. 60/124,146 filed on 1999-03-12, Application No.U.S. 60/167,061 filed on 1999-11-23, Application No. U.S. 60/124,093filed on 1999-03-12, Application No. U.S. 60/166,989 filed on1999-11-23, Application No. U.S. 60/124,145 filed on 1999-03-12,Application No. U.S. 60/168,654 filed on 1999-12-03, Application No.U.S. 60/124,099 filed on 1999-03-12, Application No. U.S. 60/168,661filed on 1999-12-03, Application No. U.S. 60/124,096 filed on1999-03-12, Application No. U.S. 60/168,622 filed on 1999-12-03,Application No. U.S. 60/124,143 filed on 1999-03-12, Application No.U.S. 60/168,663 filed on 1999-12-03, Application No. U.S. 60/124,095filed on 1999-03-12, Application No. U.S. 60/138,598 filed on1999-06-11, Application No. U.S. 60/168,665 filed on 1999-12-03,Application No. U.S. 60/125,360 filed on 1999-03-19, Application No.U.S. 60/138,626 filed on 1999-06-11, Application No. U.S. 60/168,662filed on 1999-12-03, Application No. U.S. 60/124,144 filed on1999-03-12, Application No. U.S. 60/138,574 filed on 1999-06-11,Application No. U.S. 60/168,667 filed on 1999-12-03, Application No.U.S. 60/124,142 filed on 1999-03-12, Application No. U.S. 60/138,597filed on 1999-06-11, Application No. U.S. 60/168,666 filed on1999-12-03, Application No. U.S. 60/125,359 filed on 1999-03-19,Application No. U.S. 60/168,664 filed on 1999-12-03, Application No.U.S. 60/126,051 filed on 1999-03-23, Application No. U.S. 60/169,906filed on 1999-12-10, Application No. U.S. 60/125,362 filed on1999-03-19, Application No. U.S. 60/169,980 filed on 1999-12-10,Application No. U.S. 60/125,361 filed on 1999-03-19, Application No.U.S. 60/169,910 filed on 1999-12-10, Application No. U.S. 60/125,812filed on 1999-03-23, Application No. U.S. 60/169,936 filed on1999-12-10, Application No. U.S. 60/126,054 filed on 1999-03-23,Application No. U.S. 60/169,916 filed on 1999-12-10, Application No.U.S. 60/125,815 filed on 1999-03-23, Application No. U.S. 60/169,946filed on 1999-12-10, Application No. U.S. 60/125,358 filed on1999-03-19, Application No. U.S. 60/169,616 filed on 1999-12-08,Application No. U.S. 60/125,364 filed on 1999-03-19, Application No.U.S. 60/169,623 filed on 1999-12-08, Application No. U.S. 60/125,363filed on 1999-03-19, Application No. U.S. 60/169,617 filed on1999-12-08, Application No. U.S. 60/126,502 filed on 1999-03-26,Application No. U.S. 60/172,410 filed on 1999-12-17, Application No.U.S. 60/126,503 filed on 1999-03-26, Application No. U.S. 60/172,409filed on 1999-12-17, Application No. U.S. 60/126,505 filed on1999-03-26, Application No. U.S. 60/172,412 filed on 1999-12-17,Application No. U.S. 60/126,594 filed on 1999-03-26, Application No.U.S. 60/172,408 filed on 1999-12-17, Application No. U.S. 60/126,511filed on 1999-03-26, Application No. U.S. 60/172,413 filed on1999-12-17, Application No. U.S. 60/126,595 filed on 1999-03-26,Application No. U.S. 60/171,549 filed on 1999-12-22, Application No.U.S. 60/126,598 filed on 1999-03-26, Application No. U.S. 60/171,504filed on 1999-12-22, Application No. U.S. 60/126,596 filed on1999-03-26, Application No. U.S. 60/171,552 filed on 1999-12-22,Application No. U.S. 60/126,600 filed on 1999-03-26, Application No.U.S. 60/171,550 filed on 1999-12-22, Application No. U.S. 60/126,501filed on 1999-03-26, Application No. U.S. 60/171,551 filed on1999-12-22, Application No. U.S. 60/126,504 filed on 1999-03-26,Application No. U.S. 60/174,847 filed on 2000-01-07, Application No.U.S. 60/126,509 filed on 1999-03-26, Application No. U.S. 60/174,853filed on 2000-01-07, Application No. U.S. 60/126,506 filed on1999-03-26, Application No. U.S. 60/174,852 filed on 2000-01-07,Application No. U.S. 60/242,710 filed on 2000-10-25, Application No.U.S. 60/126,510 filed on 1999-03-26, Application No. U.S. 60/174,850filed on 2000-01-07, Application No. U.S. 60/138,573 filed on1999-06-11, Application No. U.S. 60/174,851 filed on 2000-01-07,Application No. U.S. 60/126,508 filed on 1999-03-26, Application No.U.S. 60/174,871 filed on 2000-01-07, Application No. U.S. 60/126,507filed on 1999-03-26, Application No. U.S. 60/174,872 filed on2000-01-07, Application No. U.S. 60/126,597 filed on 1999-03-26,Application No. U.S. 60/174,877 filed on 2000-01-07, Application No.U.S. 60/126,601 filed on 1999-03-26, Application No. U.S. 60/154,373filed on 1999-09-17, Application No. U.S. 60/176,064 filed on2000-01-14, Application No. U.S. 60/126,602 filed on 1999-03-26,Application No. U.S. 60/176,063 filed on 2000-01-14, Application No.U.S. 60/128,695 filed on 1999-04-09, Application No. U.S. 60/176,052filed on 2000-01-14, Application No. U.S. 60/128,696 filed on1999-04-09, Application No. U.S. 60/176,069 filed on 2000-01-14,Application No. U.S. 60/128,703 filed on 1999-04-09, Application No.U.S. 60/176,068 filed on 2000-01-14, Application No. U.S. 60/128,697filed on 1999-04-09, Application No. U.S. 60/176,929 filed on2000-01-20, Application No. U.S. 60/128,698 filed on 1999-04-09,Application No. U.S. 60/176,926 filed on 2000-01-20, Application No.U.S. 60/128,699 filed on 1999-04-09, Application No. U.S. 60/177,050filed on 2000-01-20, Application No. U.S. 60/128,701 filed on1999-04-09, Application No. U.S. 60/177,166 filed on 2000-01-20,Application No. U.S. 60/128,700 filed on 1999-04-09, Application No.U.S. 60/176,930 filed on 2000-01-20, Application No. U.S. 60/128,694filed on 1999-04-09, Application No. U.S. 60/176,931 filed on2000-01-20, Application No. U.S. 60/128,702 filed on 1999-04-09,Application No. U.S. 60/177,049 filed on 2000-01-20, Application No.U.S. 60/138,629 filed on 1999-06-11, Application No. U.S. 60/138,628filed on 1999-06-11, Application No. U.S. 60/138,631 filed on1999-06-11, Application No. U.S. 60/138,632 filed on 1999-06-11,Application No. U.S. 60/138,599 filed on 1999-06-11, Application No.U.S. 60/138,572 filed on 1999-06-11, Application No. U.S. 60/138,625filed on 1999-06-11, Application No. U.S. 60/138,633 filed on1999-06-11, Application No. U.S. 60/138,630 filed on 1999-06-11,Application No. U.S. 60/138,627 filed on 1999-06-11, Application No.U.S. 60/155,808 filed on 1999-09-27, Application No. U.S. 60/155,804filed on 1999-09-27, Application No. U.S. 60/155,807 filed on1999-09-27, Application No. U.S. 60/155,805 filed on 1999-09-27,Application No. U.S. 60/155,806 filed on 1999-09-27, Application No.U.S. 60/201,194 filed on 2000-05-O₂, and Application No. U.S. 60/212,142filed on 2000-06-16. LENGTHY TABLE The patent application contains alengthy table section. A copy of the table is available in electronicform from the USPTO web site(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070048297A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. Use of a polypeptide for the preparation of a diagnostic orpharmaceutical composition for diagnosing or treating a medicalcondition, wherein said polypeptide comprises an amino acid sequence atleast 95% identical to a sequence selected from the group consisting of:(a) a full length polypeptide of SEQ ID NO:Y or a full lengthpolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (b) a predictedsecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (c) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(d) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A, wherein said fragment has biologicalactivity; (e) a polypeptide domain of SEQ ID NO:Y as referenced in Table1B; (f) a polypeptide domain of SEQ ID NO:Y as referenced in Table 2;and (g) a predicted epitope of SEQ ID NO:Y as referenced in Table 1B. 2.Use of the polypeptide of claim 1, wherein said wherein said polypeptidecomprises a heterologous amino acid sequence.
 3. Use of a polypeptidefor the preparation of a diagnostic or pharmaceutical composition fordiagnosing or treating a medical condition, wherein said polypeptidecomprises an amino acid sequence selected from the group consisting of:(a) a full length polypeptide of SEQ ID NO:Y or a full lengthpolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (b) a predictedsecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (c) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(d) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A, wherein said fragment has biologicalactivity; (e) a polypeptide domain of SEQ ID NO:Y as referenced in Table1B; (f) a polypeptide domain of SEQ ID NO:Y as referenced in Table 2;and (g) a predicted epitope of SEQ ID NO:Y as referenced in Table 1B. 4.Use of the polypeptide of claim 3, wherein said polypeptide comprises aheterologous amino acid sequence.
 5. Use of an antibody or fragmentthereof for the preparation of a diagnostic or pharmaceuticalcomposition for diagnosing or treating a medical condition, wherein saidantibody or fragment thereof binds a polypeptide comprising an aminoacid sequence at least 95% identical to a sequence selected from thegroup consisting of: (a) a full length polypeptide of SEQ ID NO:Y or afull length polypeptide encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (b) apredicted secreted form of SEQ ID NO:Y or a secreted form of thepolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded bythe cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (d) a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (e) a polypeptide domain of SEQ ID NO:Y as referenced in Table 1B; (f) a polypeptide domain of SEQ ID NO:Y asreferenced in Table 2; and (g) a predicted epitope of SEQ ID NO:Y asreferenced in Table 1B.
 6. Use of an antibody or fragment thereof forthe preparation of a diagnostic or pharmaceutical composition fordiagnosing or treating a medical condition, wherein said antibody orfragment thereof binds a polypeptide selected from the group consistingof: (a) a full length polypeptide of SEQ ID NO:Y or a full lengthpolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (b) a predictedsecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (c) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(d) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A, wherein said fragment has biologicalactivity; (e) a polypeptide domain of SEQ ID NO:Y as referenced in Table1B; (f) a polypeptide domain of SEQ ID NO:Y as referenced in Table 2;and (g) a predicted epitope of SEQ ID NO:Y as referenced in Table 1B. 7.Use of a nucleic acid molecule for the preparation of a diagnostic orpharmaceutical composition for diagnosing or treating a medicalcondition, wherein said nucleic acid molecule comprises a polynucleotidesequence at least 95% identical to a sequence selected from the groupconsisting of: (a) a polynucleotide fragment of SEQ ID NO:X asreferenced in Table 1A; (b) a polynucleotide encoding a full lengthpolypeptide of SEQ ID NO:Y or a full length polypeptide encoded by thecDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (c) a polynucleotide encoding a predictedsecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (d) a polynucleotide encoding apolypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded bythe cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (e) a polynucleotide encoding a polypeptidefragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNAClone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A, wherein said fragment has biological activity;(f) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y asreferenced in Table 1B; (g) a polynucleotide encoding a polypeptidedomain of SEQ ID NO:Y as referenced in Table 2; and (h) a polynucleotideencoding a predicted epitope of SEQ ID NO:Y as referenced in Table 1B.8. Use of the nucleic acid molecule of claim 7, wherein said nucleicacid molecule comprises a heterologous polynucleotide sequence.
 9. Useof a nucleic acid molecule for the preparation of a diagnostic orpharmaceutical composition for diagnosing or treating a medicalcondition, wherein said nucleic acid molecule comprises a polynucleotidesequence selected from the group consisting of: (a) a polynucleotidefragment of SEQ ID NO:X as referenced in Table 1A; (b) a polynucleotideencoding a full length polypeptide of SEQ ID NO:Y or a full lengthpolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolynucleotide encoding a predicted secreted form of SEQ ID NO:Y or asecreted form of the polypeptide encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(d) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (e) apolynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (f) a polynucleotide encoding apolypeptide domain of SEQ ID NO:Y as referenced in Table 1B; (g) apolynucleotide encoding a polypeptide domain of SEQ ID NO:Y asreferenced in Table 2; and (h) a polynucleotide encoding a predictedepitope of SEQ ID NO:Y as referenced in Table 1B.
 10. Use of the nucleicacid molecule of claim 9, wherein said nucleic acid molecule comprises aheterologous polynucleotide sequence.
 11. Use of an agonist orantagonist for the preparation of a pharmaceutical composition fortreating a medical condition, wherein said agonist or antagonist binds apolypeptide comprising an amino acid sequence at least 95% identical toa sequence selected from the group consisting of: (a) a full lengthpolypeptide of SEQ ID NO:Y or a full length polypeptide encoded by thecDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (b) a predicted secreted form of SEQ ID NO:Y ora secreted form of the polypeptide encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(c) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (d) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A,wherein said fragment has biological activity; (e) a polypeptide domainof SEQ ID NO:Y as referenced in Table 1B; (f) a polypeptide domain ofSEQ ID NO:Y as referenced in Table 2; and (g) a predicted epitope of SEQID NO:Y as referenced in Table 1B.
 12. Use of an agonist or antagonistfor the preparation of a pharmaceutical composition for treating amedical condition, wherein said agonist or antagonist binds apolypeptide selected from the group consisting of: (a) a full lengthpolypeptide of SEQ ID NO:Y or a full length polypeptide encoded by thecDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (b) a predicted secreted form of SEQ ID NO:Y ora secreted form of the polypeptide encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(c) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (d) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A,wherein said fragment has biological activity; (e) a polypeptide domainof SEQ ID NO:Y as referenced in Table 1B; (f) a polypeptide domain ofSEQ ID NO:Y as referenced in Table 2; and (g) a predicted epitope of SEQID NO:Y as referenced in Table 1B.
 13. A polypeptide comprising an aminoacid sequence at least 95% identical to a sequence selected from thegroup consisting of: (a) a full length polypeptide of SEQ ID NO:Y or afull length polypeptide encoded by the cDNA Clone ID in ATCC Deposit No:Z corresponding to SEQ ID NO:Y as referenced in Table 1A; (b) apredicted secreted form of SEQ ID NO:Y or a secreted form of thepolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded bythe cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (d) a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (e) a polypeptide domain of SEQ IDNO:Y as referenced in Table 1B; (f) a polypeptide domain of SEQ ID NO:Yas referenced in Table 2; and (g) a predicted epitope of SEQ ID NO:Y asreferenced in Table 1B.
 14. The polypeptide of claim 13, wherein saidpolypeptide comprises a heterologous amino acid sequence.
 15. Use of thepolypeptide of claim 13 for identifying a binding partner comprising:(a) contacting the polypeptide of claim 13 with a binding partner; and(b) determining whether the binding partner increases or decreasesactivity of the polypeptide.
 16. A polypeptide comprising an amino acidsequence selected from the group consisting of: (a) a full lengthpolypeptide of SEQ ID NO:Y or a full length polypeptide encoded by thecDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (b) a predicted secreted form of SEQ ID NO:Y ora secreted form of the polypeptide encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(c) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (d) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A,wherein said fragment has biological activity; (e) a polypeptide domainof SEQ ID NO:Y as referenced in Table 1B; (f) a polypeptide domain ofSEQ ID NO:Y as referenced in Table 2; and (g) a predicted epitope of SEQID NO:Y as referenced in Table 1B.
 17. The polypeptide of claim 16,wherein said polypeptide comprises a heterologous polypeptide sequence.18. Use of the polypeptide of claim 16 for identifying a binding partnercomprising: (a) contacting the polypeptide of claim 16 with a bindingpartner; and (b) determining whether the binding partner increases ordecreases activity of the polypeptide.
 19. An antibody or fragmentthereof that binds a polypeptide comprising an amino acid sequence atleast 95% identical to a sequence selected from the group consisting of:(a) a full length polypeptide of SEQ ID NO:Y or a full lengthpolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (b) a predictedsecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (c) a polypeptide fragment of SEQ IDNO:Y or a polypeptide fragment encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(d) a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragmentencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A, wherein said fragment has biologicalactivity; (e) a polypeptide domain of SEQ ID NO:Y as referenced in Table1B; (f) a polypeptide domain of SEQ ID NO:Y as referenced in Table 2;and (g) a predicted epitope of SEQ ID NO:Y as referenced in Table 1B.20. An antibody or fragment thereof that binds a polypeptide selectedfrom the group consisting of: (a) a full length polypeptide of SEQ IDNO:Y or a full length polypeptide encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(b) a predicted secreted form of SEQ ID NO:Y or a secreted form of thepolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded bythe cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (d) a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (e) a polypeptide domain of SEQ IDNO:Y as referenced in Table 1B; (f) a polypeptide domain of SEQ ID NO:Yas referenced in Table 2; and (g) a predicted epitope of SEQ ID NO:Y asreferenced in Table 1B.
 21. A nucleic acid molecule comprising apolynucleotide sequence at least 95% identical to a sequence selectedfrom the group consisting of: (a) a polynucleotide fragment of SEQ IDNO:X as referenced in Table 1A; (b) a polynucleotide encoding a fulllength polypeptide of SEQ ID NO:Y or a full length polypeptide encodedby the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Yas referenced in Table 1A; (c) a polynucleotide encoding a predictedsecreted form of SEQ ID NO:Y or a secreted form of the polypeptideencoded by the cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQID NO:Y as referenced in Table 1A; (d) a polynucleotide encoding apolypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded bythe cDNA Clone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A; (e) a polynucleotide encoding a polypeptidefragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNAClone ID in ATCC Deposit No: Z corresponding to SEQ ID NO:Y asreferenced in Table 1A, wherein said fragment has biological activity;(f) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y asreferenced in Table 1B; (g) a polynucleotide encoding a polypeptidedomain of SEQ ID NO:Y as referenced in Table 2; and (h) a polynucleotideencoding a predicted epitope of SEQ ID NO:Y as referenced in Table 1B.22. The nucleic acid molecule of claim 21, wherein said nucleic acidmolecule comprises a heterologous polynucleotide sequence.
 23. Arecombinant vector comprising the nucleic acid molecule of claim
 21. 24.A recombinant vector comprising the nucleic acid molecule of claim 22.25. A recombinant host cell comprising the recombinant vector of claim23.
 26. A recombinant host cell comprising the recombinant vector ofclaim
 24. 27. A nucleic acid molecule comprising a polynucleotidesequence selected from the group consisting of: (a) a polynucleotidefragment of SEQ ID NO:X as referenced in Table 1A; (b) a polynucleotideencoding a full length polypeptide of SEQ ID NO:Y or a full lengthpolypeptide encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (c) apolynucleotide encoding a predicted secreted form of SEQ ID NO:Y or asecreted form of the polypeptide encoded by the cDNA Clone ID in ATCCDeposit No: Z corresponding to SEQ ID NO:Y as referenced in Table 1A;(d) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A; (e) apolynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or apolypeptide fragment encoded by the cDNA Clone ID in ATCC Deposit No: Zcorresponding to SEQ ID NO:Y as referenced in Table 1A, wherein saidfragment has biological activity; (f) a polynucleotide encoding apolypeptide domain of SEQ ID NO:Y as referenced in Table 1B; (g) apolynucleotide encoding a polypeptide domain of SEQ ID NO:Y asreferenced in Table 2; and (h) a polynucleotide encoding a predictedepitope of SEQ ID NO:Y as referenced in Table 1B.
 28. The nucleic acidmolecule of claim 27, wherein said nucleic acid molecule comprises aheterologous polynucleotide sequence.
 29. A recombinant vectorcomprising the nucleic acid molecule of claim
 27. 30. A recombinantvector comprising the nucleic acid molecule of claim
 28. 31. Arecombinant host cell comprising the recombinant vector of claim
 29. 32.A recombinant host cell comprising the recombinant vector of claim 30.